33 results on '"Maria Kousi"'
Search Results
2. Mutations in ATP13A2 (PARK9) are associated with an amyotrophic lateral sclerosis-like phenotype, implicating this locus in further phenotypic expansion
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Rossella Spataro, Maria Kousi, Sali M. K. Farhan, Jason R. Willer, Jay P. Ross, Patrick A. Dion, Guy A. Rouleau, Mark J. Daly, Benjamin M. Neale, Vincenzo La Bella, and Nicholas Katsanis
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Medicine ,Genetics ,QH426-470 - Abstract
Abstract Background Amyotrophic lateral sclerosis [1] is a genetically heterogeneous neurodegenerative disorder, characterized by late-onset degeneration of motor neurons leading to progressive limb and bulbar weakness, as well as of the respiratory muscles, which is the primary cause of disease fatality. To date, over 25 genes have been implicated as causative in ALS with C9orf72, SOD1, FUS, and TARDBP accounting for the majority of genetically positive cases. Results We identified two patients of Italian and French ancestry with a clinical diagnosis of juvenile-onset ALS who were mutation-negative in any of the known ALS causative genes. Starting with the index case, a consanguineous family of Italian origin, we performed whole-exome sequencing and identified candidate pathogenic mutations in 35 genes, 27 of which were homozygous. We next parsed all candidates against a cohort of 3641 ALS cases; only ATP13A2 was found to harbor recessive changes, in a patient with juvenile-onset ALS, similar to the index case. In vivo complementation of ATP13A2 using a zebrafish surrogate model that focused on the assessment of motor neuron morphology and cerebellar integrity confirmed the role of this gene in central and peripheral nervous system maintenance and corroborated the damaging direction of effect of the change detected in the index case of this study. Conclusions We here expand the phenotypic spectrum associated with genetic variants in ATP13A2 that previously comprised Kufor-Rakeb syndrome, spastic paraplegia 78, and neuronal ceroid lipofuscinosis type 12 (CLN12), to also include juvenile-onset ALS, as supported by both genetic and functional data. Our findings highlight the importance of establishing a complete genetic profile towards obtaining an accurate clinical diagnosis.
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- 2019
- Full Text
- View/download PDF
3. Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy
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Claudia Gonzaga-Jauregui, Tamar Harel, Tomasz Gambin, Maria Kousi, Laurie B. Griffin, Ludmila Francescatto, Burcak Ozes, Ender Karaca, Shalini N. Jhangiani, Matthew N. Bainbridge, Kim S. Lawson, Davut Pehlivan, Yuji Okamoto, Marjorie Withers, Pedro Mancias, Anne Slavotinek, Pamela J. Reitnauer, Meryem T. Goksungur, Michael Shy, Thomas O. Crawford, Michel Koenig, Jason Willer, Brittany N. Flores, Igor Pediaditrakis, Onder Us, Wojciech Wiszniewski, Yesim Parman, Anthony Antonellis, Donna M. Muzny, Nicholas Katsanis, Esra Battaloglu, Eric Boerwinkle, Richard A. Gibbs, and James R. Lupski
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Biology (General) ,QH301-705.5 - Abstract
Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous distal symmetric polyneuropathy. Whole-exome sequencing (WES) of 40 individuals from 37 unrelated families with CMT-like peripheral neuropathy refractory to molecular diagnosis identified apparent causal mutations in ∼45% (17/37) of families. Three candidate disease genes are proposed, supported by a combination of genetic and in vivo studies. Aggregate analysis of mutation data revealed a significantly increased number of rare variants across 58 neuropathy-associated genes in subjects versus controls, confirmed in a second ethnically discrete neuropathy cohort, suggesting that mutation burden potentially contributes to phenotypic variability. Neuropathy genes shown to have highly penetrant Mendelizing variants (HPMVs) and implicated by burden in families were shown to interact genetically in a zebrafish assay exacerbating the phenotype established by the suppression of single genes. Our findings suggest that the combinatorial effect of rare variants contributes to disease burden and variable expressivity.
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- 2015
- Full Text
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4. Single-cell mosaicism analysis reveals cell-type-specific somatic mutational burden in Alzheimer’s Dementia
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Maria Kousi, Carles Boix, Yongjin P. Park, Hansruedi Mathys, Samuel Sledzieski, Zhuyu Peng, David A. Bennett, Li-Huei Tsai, and Manolis Kellis
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Despite significant advances in identifying genetic drivers of neurodegenerative disorders, the majority of affected individuals lack molecular genetic diagnosis, with somatic mutations proposed as one potential contributor to increased risk. Here, we report the first cell-type-specific map of somatic mosaicism in Alzheimer’s Dementia (AlzD), using 4,014 cells from prefrontal cortex samples of 19 AlzD and 17 non-AlzD individuals. We integrate full-transcript single-nucleus RNA-seq (SMART-Seq) with matched individual-level whole-genome sequencing to jointly infer mutational events and the cell-type in which they occurred. AlzD individuals show increased mutational burden, localized in excitatory neurons, oligodendrocytes, astrocytes and disease-associated “senescent” cells. High-mutational-burden cells showed mutational enrichment and similar single-cell expression profiles in AlzD cases versus non-AlzD individuals, indicating cellular-level genotype-to-phenotype correlation. Somatic mutations are specifically enriched for known AlzD genes, and implicate biologically meaningful cell-type specific processes, including: neuronal energy regulation, endocytic trafficking (NEFM), lipid metabolism (CNP, CRYAB), proteostasis (USP34), cytoskeleton, and microtubule dynamics (MACF1).
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- 2022
5. PCM1 is necessary for focal ciliary integrity and is a candidate for severe schizophrenia
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Larry S. Barak, Richard A. Gibbs, Yushi Bai, Maria Kousi, Tanner O. Monroe, Karen Soldano, Jeremiah Savage, Sungjin Moon, Ramona M. Rodriguiz, Steven C. Brodar, Thomas Hansen, Melanie E. Garrett, Donna M. Muzny, Nicholas Katsanis, Akira Sawa, William C. Wetsel, Allison E. Ashley-Koch, Patrick F. Sullivan, and Thomas Werge
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0301 basic medicine ,Drug Resistance ,General Physics and Astronomy ,Cell Cycle Proteins ,DISEASE ,Receptors, G-Protein-Coupled ,GENETIC ASSOCIATION ,Mice ,0302 clinical medicine ,RARE ,Amines ,lcsh:Science ,Zebrafish ,HYDROCEPHALUS ,Pericentriolar material ,Mice, Knockout ,Multidisciplinary ,biology ,Disease genetics ,Cilium ,Neurogenesis ,Brain ,Middle Aged ,Phenotype ,Schizophrenia ,Behavioural genetics ,Antipsychotic Agents ,Signal Transduction ,Adult ,RECRUITMENT ,Science ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,Young Adult ,PCM1 ,Dopamine receptor D2 ,medicine ,Animals ,Humans ,CENTROSOME ,Genetic Predisposition to Disease ,Cilia ,Alleles ,METAANALYSIS ,Aged ,Receptors, Dopamine D2 ,MUTATIONS ,General Chemistry ,biology.organism_classification ,medicine.disease ,FRAMEWORK ,030104 developmental biology ,Mutation ,REPLICATION ,lcsh:Q ,Neuroscience ,030217 neurology & neurosurgery - Abstract
The neuronal primary cilium and centriolar satellites have functions in neurogenesis, but little is known about their roles in the postnatal brain. We show that ablation of pericentriolar material 1 in the mouse leads to progressive ciliary, anatomical, psychomotor, and cognitive abnormalities. RNAseq reveals changes in amine- and G-protein coupled receptor pathways. The physiological relevance of this phenotype is supported by decreased available dopamine D2 receptor (D2R) levels and the failure of antipsychotic drugs to rescue adult behavioral defects. Immunoprecipitations show an association with Pcm1 and D2Rs. Finally, we sequence PCM1 in two human cohorts with severe schizophrenia. Systematic modeling of all discovered rare alleles by zebrafish in vivo complementation reveals an enrichment for pathogenic alleles. Our data emphasize a role for the pericentriolar material in the postnatal brain, with progressive degenerative ciliary and behavioral phenotypes; and they support a contributory role for PCM1 in some individuals diagnosed with schizophrenia., The role of ciliary/centriolar components in the postnatal brain is unclear. Here, the authors show via ablation of Pcm1 in mice that degenerative ciliary/centriolar phenotypes induce neuroanatomical and behavioral changes. Sequencing of PCM1 in human cohorts and zebrafish in vivo complementation suggests PCM1 mutations can contribute to schizophrenia.
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- 2020
6. Evidence for secondary-variant genetic burden and non-random distribution across biological modules in a recessive ciliopathy
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Jill A. Rosenfeld Mokry, Shamil R. Sunyaev, Erica E. Davis, Niki Mourtzi, Maria Kousi, Richard A. Lewis, Michael E. Talkowski, Azita Sadeghpour, Onuralp Soylemez, Maxim Y Wolf, Manolis Kellis, Nicholas Katsanis, Christopher A. Cassa, Jean Muller, Kelsey McFadden, Irwin Jungreis, Sebastian Akle, Aysegul Ozanturk, Hélène Dollfus, and Harrison Brand
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Nonsynonymous substitution ,Genetics ,congenital, hereditary, and neonatal diseases and abnormalities ,0303 health sciences ,education.field_of_study ,Population ,Biology ,medicine.disease ,Genetic architecture ,03 medical and health sciences ,Ciliopathy ,symbols.namesake ,0302 clinical medicine ,medicine ,Mendelian inheritance ,symbols ,Epistasis ,Allele ,education ,Gene ,030217 neurology & neurosurgery ,030304 developmental biology - Abstract
The influence of genetic background on driver mutations is well established; however, the mechanisms by which the background interacts with Mendelian loci remain unclear. We performed a systematic secondary-variant burden analysis of two independent cohorts of patients with Bardet-Biedl syndrome (BBS) with known recessive biallelic pathogenic mutations in one of 17 BBS genes for each individual. We observed a significant enrichment of trans-acting rare nonsynonymous secondary variants in patients with BBS compared with either population controls or a cohort of individuals with a non-BBS diagnosis and recessive variants in the same gene set. Strikingly, we found a significant over-representation of secondary alleles in chaperonin-encoding genes-a finding corroborated by the observation of epistatic interactions involving this complex in vivo. These data indicate a complex genetic architecture for BBS that informs the biological properties of disease modules and presents a model for secondary-variant burden analysis in recessive disorders.
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- 2020
7. Transcriptomics in rare diseases
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Maria Kousi
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Transcriptome ,chemistry.chemical_compound ,chemistry ,RNA splicing ,RNA ,Human genome ,Computational biology ,Biology ,Molecular diagnostics ,Phenotype ,Gene ,DNA - Abstract
The unprecedented technological advances in nucleic acid analysis methods and platforms of the past two decades have enabled the interrogation not only of the human genome but also of its transcriptome at a high degree of granularity. From the original analysis of short sequences to arrays encompassing all known genes and more recently high-throughput sequencing methodologies, transcriptomics has offered a unique insight into the regulation and translation of human variation from the deoxyribonucleic acid (DNA) level toward protein expression. Combinatorial analyses of DNA and ribonucleic acid (RNA) sequencing have improved genetic diagnostic yield for some phenotypes, due to the opportunity that RNA sequencing (RNA-seq) offers in detecting disease-relevant mechanisms that had remained invisible through DNA analyses alone. Prominent examples involve aberrant and often tissue-specific splicing, differential expression of genes in disease-derived tissues compared to control profiles, and cases of monoallelic expression of disease variants, a phenomenon through which heterozygous DNA variants can mimic a recessive state. Despite the fact that transcriptomic analyses represent a snapshot of cellular biology in time, they offer an orthogonal view into how DNA variant information translates into disease biology. As current transcriptomic limitations such as experimental variability, access to relevant tissues, and assembly of adequate control populations improve, our understanding of rare diseases will also likely broaden. This chapter provides an overview of the methodologies used to study the human transcriptome, reviews the knowledge emerging from recent discoveries that successfully demonstrate the utility of RNA-seq in diagnosing rare disorders, and offers a balanced discussion on the next hurdles that need to be overcome in order to maximize the potential utility of this approach in studying the biology of disease and potentially for molecular diagnostics.
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- 2021
8. List of contributors
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Amy Breman, Karlla Welch Brigatti, Maria Chahrour, Giusy Della Gatta, Bracha Erlanger Avigdor, Lauretta El Hayek, Claudia Gonzaga-Jauregui, Maria Kousi, Ikeoluwa A. Osei-Owusu, Jonathan Pevsner, Jennifer E. Posey, Erik G. Puffenberger, Paweł Stankiewicz, Cristopher V. Van Hout, and Cinthya J. Zepeda Mendoza
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- 2021
9. Transcriptome-wide association study of schizophrenia and chromatin activity yields mechanistic disease insights
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Daniel H. Geschwind, Nicholas Mancuso, Steven A. McCarroll, Hilary K. Finucane, Nicholas Katsanis, Gregory E. Crawford, Alkes L. Price, Lingyun Song, Patrick F. Sullivan, Hyejung Won, Alexias Safi, Roel A. Ophoff, Yakir A. Reshef, Bogdan Pasaniuc, Maria Kousi, Alexander Gusev, Benjamin M. Neale, and Michael Conlon O'Donovan
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0301 basic medicine ,Multifactorial Inheritance ,Quantitative Trait Loci ,Gene Dosage ,Kinesins ,Locus (genetics) ,Genomics ,Genome-wide association study ,Computational biology ,Biology ,Quantitative trait locus ,Article ,Transcriptome ,03 medical and health sciences ,Genetics ,Animals ,Humans ,Genetic Predisposition to Disease ,Protein Phosphatase 2 ,Zebrafish ,Epigenomics ,Mitogen-Activated Protein Kinase 3 ,Gene Expression Profiling ,Brain ,Zebrafish Proteins ,Chromatin ,3. Good health ,Gene expression profiling ,030104 developmental biology ,Schizophrenia ,Microtubule-Associated Proteins ,Genome-Wide Association Study - Abstract
Genome-wide association studies (GWAS) have identified over 100 risk loci for schizophrenia, but the causal mechanisms remain largely unknown. We performed a transcriptome-wide association study (TWAS) integrating a schizophrenia GWAS of 79,845 individuals from the Psychiatric Genomics Consortium with expression data from brain, blood, and adipose tissues across 3,693 primarily control individuals. We identified 157 TWAS-significant genes, of which 35 did not overlap a known GWAS locus. Of these 157 genes, 42 were associated with specific chromatin features measured in independent samples, thus highlighting potential regulatory targets for follow-up. Suppression of one identified susceptibility gene, mapk3, in zebrafish showed a significant effect on neurodevelopmental phenotypes. Expression and splicing from the brain captured most of the TWAS effect across all genes. This large-scale connection of associations to target genes, tissues, and regulatory features is an essential step in moving toward a mechanistic understanding of GWAS.
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- 2018
10. Performance of computational methods for the evaluation of Pericentriolar Material 1 missense variants in CAGI-5
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Marco Carraro, Maria Kousi, Yanran Wang, Rita Casadio, Pier Luigi Martelli, Castrense Savojardo, Emidio Capriotti, Luigi Chiricosta, Giulia Babbi, Alexander Miguel Monzon, Steven E. Brenner, James Han, Panagiotis Katsonis, Kivilcim Ozturk, Nicholas Katsanis, Emanuela Leonardi, Olivier Lichtarge, Gaia Andreoletti, Hannah Carter, Silvio C. E. Tosatto, John Moult, Carlo Ferrari, Maximilian Miller, Francesco Reggiani, Yana Bromberg, Monzon A.M., Carraro M., Chiricosta L., Reggiani F., Han J., Ozturk K., Wang Y., Miller M., Bromberg Y., Capriotti E., Savojardo C., Babbi G., Martelli P.L., Casadio R., Katsonis P., Lichtarge O., Carter H., Kousi M., Katsanis N., Andreoletti G., Moult J., Brenner S.E., Ferrari C., Leonardi E., and Tosatto S.C.E.
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bioinformatics tools ,community challenge ,critical assessment ,effect prediction ,missense mutations ,variant interpretation ,Cell Cycle Proteins ,Autoantigens ,Databases, Genetic ,2.1 Biological and endogenous factors ,Missense mutation ,Aetiology ,Genetics (clinical) ,Pericentriolar material ,Genetics & Heredity ,0303 health sciences ,030305 genetics & heredity ,Single Nucleotide ,Mental Health ,Phenotype ,Mutation (genetic algorithm) ,Critical assessment ,Neural Networks ,Clinical Sciences ,Mutation, Missense ,Single-nucleotide polymorphism ,Computational biology ,Biology ,Polymorphism, Single Nucleotide ,Article ,Databases ,Computer ,03 medical and health sciences ,Genetic ,Genetics ,Humans ,Genetic Predisposition to Disease ,Polymorphism ,Clinical phenotype ,Gene ,Loss function ,030304 developmental biology ,missense mutation ,Computational Biology ,Brain Disorders ,Mutation ,bioinformatics tool ,Schizophrenia ,Neural Networks, Computer ,Missense - Abstract
The CAGI-5 pericentriolar material 1 (PCM1) challenge aimed to predict the effect of 38 transgenic human missense mutations in the PCM1 protein implicated in schizophrenia. Participants were provided with 16 benign variants (negative controls), 10 hypomorphic, and 12 loss of function variants. Six groups participated and were asked to predict the probability of effect and standard deviation associated to each mutation. Here, we present the challenge assessment. Prediction performance was evaluated using different measures to conclude in a final ranking which highlights the strengths and weaknesses of each group. The results show a great variety of predictions where some methods performed significantly better than others. Benign variants played an important role as negative controls, highlighting predictors biased to identify disease phenotypes. The best predictor, Bromberg lab, used a neural-network-based method able to discriminate between neutral and non-neutral single nucleotide polymorphisms. The CAGI-5 PCM1 challenge allowed us to evaluate the state of the art techniques for interpreting the effect of novel variants for a difficult target protein.
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- 2019
11. Biallelic SQSTM1 mutations in early-onset, variably progressive neurodegeneration
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Teresa Rizza, Reza Maroofian, Amir Sherafat, Jawaher Zeighami, Francesca Pantaleoni, Serena Cecchetti, Aaron R. Jeffries, Valentina Muto, Simone Martinelli, Yalda Jamshidi, Neda Mazaheri, Reza Azizi Malamiri, Rosalba Carrozzo, Viviana Caputo, Giovanna Carpentieri, Marco Tartaglia, Elisabetta Flex, Hamid Galehdari, Mohammadreza Dehghani, Michela Di Nottia, Andrea Ciolfi, Mohammad Yahya Vahidi Mehrjardi, Guido Primiano, Serenella Servidei, Daniela Di Giuda, Maria Kousi, Zachary A. Kupchinsky, Alice Traversa, Nicholas Katsanis, Gholam Reza Shariati, and Alireza Sedaghat
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0301 basic medicine ,autophagy ,Ataxia ,Protein degradation ,Biology ,Gene mutation ,medicine.disease_cause ,early-onset neurodegeneration ,03 medical and health sciences ,0302 clinical medicine ,Sequestosome 1 ,early-onset neurodegeneration, ataxia, SQSTM1, autophagy, ubiquitined protein aggregates ,medicine ,SQSTM1 ,Cognitive decline ,education ,Exome sequencing ,Genetics ,Mutation ,education.field_of_study ,ataxia ,Disease gene identification ,ubiquitined protein aggregates ,Settore MED/26 - NEUROLOGIA ,whole-exome sequencing ,neurodegenerative disorder ,030104 developmental biology ,Neurology (clinical) ,medicine.symptom ,030217 neurology & neurosurgery - Abstract
ObjectiveTo characterize clinically and molecularly an early-onset, variably progressive neurodegenerative disorder characterized by a cerebellar syndrome with severe ataxia, gaze palsy, dyskinesia, dystonia, and cognitive decline affecting 11 individuals from 3 consanguineous families.MethodsWe used whole-exome sequencing (WES) (families 1 and 2) and a combined approach based on homozygosity mapping and WES (family 3). We performed in vitro studies to explore the effect of the nontruncating SQSTM1 mutation on protein function and the effect of impaired SQSTM1 function on autophagy. We analyzed the consequences of sqstm1 down-modulation on the structural integrity of the cerebellum in vivo using zebrafish as a model.ResultsWe identified 3 homozygous inactivating variants, including a splice site substitution (c.301+2T>A) causing aberrant transcript processing and accelerated degradation of a resulting protein lacking exon 2, as well as 2 truncating changes (c.875_876insT and c.934_936delinsTGA). We show that loss of SQSTM1 causes impaired production of ubiquitin-positive protein aggregates in response to misfolded protein stress and decelerated autophagic flux. The consequences of sqstm1 down-modulation on the structural integrity of the cerebellum in zebrafish documented a variable but reproducible phenotype characterized by cerebellum anomalies ranging from depletion of axonal connections to complete atrophy. We provide a detailed clinical characterization of the disorder; the natural history is reported for 2 siblings who have been followed up for >20 years.ConclusionsThis study offers an accurate clinical characterization of this recently recognized neurodegenerative disorder caused by biallelic inactivating mutations in SQSTM1 and links this phenotype to defective selective autophagy.
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- 2019
12. Mutations in ATP13A2 (PARK9) are associated with an amyotrophic lateral sclerosis-like phenotype, implicating this locus in further phenotypic expansion
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Maria Kousi, Jason R. Willer, Vincenzo La Bella, Guy A. Rouleau, Jay P. Ross, Patrick A. Dion, Sali M.K. Farhan, Mark J. Daly, Nicholas Katsanis, Benjamin M. Neale, Rossella Spataro, Spataro R, Kousi M, Farhan SMK, Willer JR, Ross JP, Dion PA, Rouleau GA, Daly MJ, Neale BM, La Bella V, Katsanis N, Centre of Excellence in Complex Disease Genetics, and Institute for Molecular Medicine Finland
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Male ,Amyotrophic lateral sclerosis, ATP13A2, parkinsonism ,lcsh:Medicine ,0302 clinical medicine ,C9orf72 ,Drug Discovery ,Amyotrophic lateral sclerosis ,Index case ,Zebrafish ,Exome sequencing ,Motor Neurons ,Genetics ,0303 health sciences ,DEMENTIA ,1184 Genetics, developmental biology, physiology ,Middle Aged ,Pedigree ,3. Good health ,Proton-Translocating ATPases ,Phenotype ,Molecular Medicine ,Female ,Settore MED/26 - Neurologia ,Primary Research ,Adult ,lcsh:QH426-470 ,SOD1 ,Biology ,TARDBP ,03 medical and health sciences ,Parkinsonian Disorders ,Neuronal Ceroid-Lipofuscinoses ,Exome Sequencing ,medicine ,Animals ,Humans ,Genetic Predisposition to Disease ,Molecular Biology ,030304 developmental biology ,Genetic heterogeneity ,Amyotrophic Lateral Sclerosis ,lcsh:R ,medicine.disease ,Disease Models, Animal ,lcsh:Genetics ,Mutation ,Neuronal ceroid lipofuscinosis ,030217 neurology & neurosurgery ,PARKINSONISM - Abstract
Background Amyotrophic lateral sclerosis [1] is a genetically heterogeneous neurodegenerative disorder, characterized by late-onset degeneration of motor neurons leading to progressive limb and bulbar weakness, as well as of the respiratory muscles, which is the primary cause of disease fatality. To date, over 25 genes have been implicated as causative in ALS with C9orf72, SOD1, FUS, and TARDBP accounting for the majority of genetically positive cases. Results We identified two patients of Italian and French ancestry with a clinical diagnosis of juvenile-onset ALS who were mutation-negative in any of the known ALS causative genes. Starting with the index case, a consanguineous family of Italian origin, we performed whole-exome sequencing and identified candidate pathogenic mutations in 35 genes, 27 of which were homozygous. We next parsed all candidates against a cohort of 3641 ALS cases; only ATP13A2 was found to harbor recessive changes, in a patient with juvenile-onset ALS, similar to the index case. In vivo complementation of ATP13A2 using a zebrafish surrogate model that focused on the assessment of motor neuron morphology and cerebellar integrity confirmed the role of this gene in central and peripheral nervous system maintenance and corroborated the damaging direction of effect of the change detected in the index case of this study. Conclusions We here expand the phenotypic spectrum associated with genetic variants in ATP13A2 that previously comprised Kufor-Rakeb syndrome, spastic paraplegia 78, and neuronal ceroid lipofuscinosis type 12 (CLN12), to also include juvenile-onset ALS, as supported by both genetic and functional data. Our findings highlight the importance of establishing a complete genetic profile towards obtaining an accurate clinical diagnosis. Electronic supplementary material The online version of this article (10.1186/s40246-019-0203-9) contains supplementary material, which is available to authorized users.
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- 2019
13. Neonatal Alexander Disease : Novel GFAP Mutation and Comparison to Previously Published Cases
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Anna-Elina Lehesjoki, Maria Kousi, Anna-Kaisa Anttonen, Maria Suo-Palosaari, Hannu Tuominen, Päivi Vieira, Johanna Uusimaa, Leena Vainionpää, Tarja Joensuu, Jukka S. Moilanen, Oula Knuutinen, Neuroscience Center, Research Programs Unit, Research Programme for Molecular Neurology, University of Helsinki, Anna-Elina Lehesjoki / Principal Investigator, Department of Medical and Clinical Genetics, and Medicum
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Male ,0301 basic medicine ,Proband ,Pathology ,medicine.medical_specialty ,leukodystrophy ,030105 genetics & heredity ,VARIANTS ,DIAGNOSIS ,PHENOTYPE ,3124 Neurology and psychiatry ,03 medical and health sciences ,Fatal Outcome ,0302 clinical medicine ,3123 Gynaecology and paediatrics ,Glial Fibrillary Acidic Protein ,medicine ,INFANTILE ,Humans ,Missense mutation ,FIBRILLARY ACIDIC PROTEIN ,Splice site mutation ,neuroimaging ,business.industry ,Leukodystrophy ,Macrocephaly ,3112 Neurosciences ,Brain ,Infant ,General Medicine ,medicine.disease ,GENE ,Hypotonia ,Alexander disease ,3. Good health ,Mutation ,Pediatrics, Perinatology and Child Health ,drug-resistant seizures ,Alexander Disease ,Neurology (clinical) ,medicine.symptom ,Age of onset ,business ,hydrocephalus ,030217 neurology & neurosurgery ,FORM - Abstract
Alexander disease (AxD) is a genetic leukodystrophy caused by GFAP mutations leading to astrocyte dysfunction. Neonatal AxD is a rare phenotype with onset in the first month of life. The proband, belonging to a large pedigree with dominantly inherited benign familial neonatal epilepsy (BFNE), had a phenotype distinct from the rest of the family, with hypotonia and macrocephaly in addition to drug-resistant neonatal seizures. The patient deteriorated and passed away at 6 weeks of age. The pathological and neuroimaging data were consistent with the diagnosis of AxD. Genetic analysis of the proband identified a novel de novo GFAP missense mutation and a KCNQ2 splice site mutation segregating with the BFNE phenotype in the family. The GFAP mutation was located in the coil 2B region of GFAP protein, similar to most neonatal-onset AxD cases with an early death. The clinical and neuroradiological features of the previously published neonatal AxD patients are presented. This study further supports the classification of neonatal-onset AxD as a distinct phenotype based on the age of onset.
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- 2018
14. Evidence for secondary-variant genetic burden and non-random distribution across biological modules in a recessive ciliopathy
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Maria, Kousi, Onuralp, Söylemez, Aysegül, Ozanturk, Niki, Mourtzi, Sebastian, Akle, Irwin, Jungreis, Jean, Muller, Christopher A, Cassa, Harrison, Brand, Jill Anne, Mokry, Maxim Y, Wolf, Azita, Sadeghpour, Kelsey, McFadden, Richard A, Lewis, Michael E, Talkowski, Hélène, Dollfus, Manolis, Kellis, Erica E, Davis, Shamil R, Sunyaev, and Nicholas, Katsanis
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Cohort Studies ,Genetic Variation ,Humans ,Exome ,Bardet-Biedl Syndrome ,Alleles - Abstract
The influence of genetic background on driver mutations is well established; however, the mechanisms by which the background interacts with Mendelian loci remain unclear. We performed a systematic secondary-variant burden analysis of two independent cohorts of patients with Bardet-Biedl syndrome (BBS) with known recessive biallelic pathogenic mutations in one of 17 BBS genes for each individual. We observed a significant enrichment of trans-acting rare nonsynonymous secondary variants in patients with BBS compared with either population controls or a cohort of individuals with a non-BBS diagnosis and recessive variants in the same gene set. Strikingly, we found a significant over-representation of secondary alleles in chaperonin-encoding genes-a finding corroborated by the observation of epistatic interactions involving this complex in vivo. These data indicate a complex genetic architecture for BBS that informs the biological properties of disease modules and presents a model for secondary-variant burden analysis in recessive disorders.
- Published
- 2018
15. Variation in a range of mTOR-related genes associates with intracranial volume and intellectual disability
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M. van Gastel, Tjitske Kleefstra, Eric Smeets, Alexander P.A. Stegmann, R. Pfundt, Nicholas Katsanis, Christian Gilissen, Ype Elgersma, Servi J. C. Stevens, M. Proietti-Onori, G. M. S. Mancini, Barbara Franke, G. M. van Woerden, Janita Bralten, Margot R.F. Reijnders, Stefan H. Lelieveld, Maria Kousi, T. van Essen, Perciliz L. Tan, Han G. Brunner, Marieke Klein, MUMC+: DA KG Lab Centraal Lab (9), Klinische Genetica, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA Klinische Genetica (5), Neurosciences, and Clinical Genetics
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0301 basic medicine ,General Physics and Astronomy ,SET ANALYSIS ,0302 clinical medicine ,MIGRATION DEFICITS ,Cell Movement ,Megalencephaly ,TUBEROUS SCLEROSIS COMPLEX ,INTRACTABLE EPILEPSY ,lcsh:Science ,Cells, Cultured ,Zebrafish ,IN-VIVO ,Genetics ,Neurons ,education.field_of_study ,Multidisciplinary ,biology ,TOR Serine-Threonine Kinases ,Brain ,Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6] ,Human brain ,Organ Size ,medicine.anatomical_structure ,MESSENGER-RNA TRANSLATION ,Brain size ,RHEB ,Signal Transduction ,Science ,Population ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,Seizures ,Intellectual Disability ,CEREBRAL-CORTEX ,medicine ,Animals ,Humans ,Allele ,education ,Gene ,PI3K/AKT/mTOR pathway ,Cell Size ,Sirolimus ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,CORTICAL DEVELOPMENT ,General Chemistry ,SOMATIC MUTATIONS ,medicine.disease ,030104 developmental biology ,MAMMALIAN TARGET ,Mutation ,biology.protein ,lcsh:Q ,Ras Homolog Enriched in Brain Protein ,030217 neurology & neurosurgery - Abstract
De novo mutations in specific mTOR pathway genes cause brain overgrowth in the context of intellectual disability (ID). By analyzing 101 mMTOR-related genes in a large ID patient cohort and two independent population cohorts, we show that these genes modulate brain growth in health and disease. We report the mTOR activator gene RHEB as an ID gene that is associated with megalencephaly when mutated. Functional testing of mutant RHEB in vertebrate animal models indicates pathway hyperactivation with a concomitant increase in cell and head size, aberrant neuronal migration, and induction of seizures, concordant with the human phenotype. This study reveals that tight control of brain volume is exerted through a large community of mTOR-related genes. Human brain volume can be altered, by either rare disruptive events causing hyperactivation of the pathway, or through the collective effects of common alleles., The mTOR pathway is a key regulator of normal brain development. Here, the authors identify de novo mutations in RHEB, an mTOR activator protein, in patients with intellectual disability associated with megalencephaly and find a role for RHEB in regulating neuronal soma size and migration in vitro and in vivo.
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- 2017
16. Mutations Impairing GSK3-Mediated MAF Phosphorylation Cause Cataract, Deafness, Intellectual Disability, Seizures, and a Down Syndrome-like Facies
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Philippe M. Campeau, Alice Traversa, Maria Teresa Fiorenza, Nicholas Katsanis, Nicole Philip, Stephen R. Braddock, Karen W. Gripp, Antonio Palleschi, Serena Cecchetti, Marcello Niceta, Carla Boitani, Lorenzo Stella, Alessandro Bruselles, Viviana Caputo, Chiara Leoni, Gabriele Gillessen-Kaesbach, Kim M. Keppler-Noreuil, Gianfranco Bocchinfuso, Maria Kousi, Takaya Nakane, Marco Tartaglia, Dmitriy Niyazov, Emilia Stellacci, Massimiliano Anselmi, Giuseppe Zampino, Celio Pouponnot, Katia Sol-Church, Deborah L. Stabley, Andrea Ciolfi, Sabrina Prudente, and Brendan Lee
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Down syndrome ,Deafness ,Biology ,Cataract ,Down Syndrome ,Glycogen Synthase Kinase 3 ,Humans ,Intellectual Disability ,Mutation ,Phenotype ,Phosphorylation ,Proto-Oncogene Proteins c-maf ,Seizures ,MAF ,mutations ,developmental defects ,aimé-gripp syndrome ,Transactivation ,Report ,Genetics ,medicine ,Missense mutation ,Genetics(clinical) ,Transcription factor ,Genetics (clinical) ,Loss function ,Settore CHIM/02 - Chimica Fisica ,medicine.disease ,AP-1 transcription factor ,Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA - Abstract
Transcription factors operate in developmental processes to mediate inductive events and cell competence, and perturbation of their function or regulation can dramatically affect morphogenesis, organogenesis, and growth. We report that a narrow spectrum of amino-acid substitutions within the transactivation domain of the v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog (MAF), a leucine zipper-containing transcription factor of the AP1 superfamily, profoundly affect development. Seven different de novo missense mutations involving conserved residues of the four GSK3 phosphorylation motifs were identified in eight unrelated individuals. The distinctive clinical phenotype, for which we propose the eponym Aymé-Gripp syndrome, is not limited to lens and eye defects as previously reported for MAF/Maf loss of function but includes sensorineural deafness, intellectual disability, seizures, brachycephaly, distinctive flat facial appearance, skeletal anomalies, mammary gland hypoplasia, and reduced growth. Disease-causing mutations were demonstrated to impair proper MAF phosphorylation, ubiquitination and proteasomal degradation, perturbed gene expression in primary skin fibroblasts, and induced neurodevelopmental defects in an in vivo model. Our findings nosologically and clinically delineate a previously poorly understood recognizable multisystem disorder, provide evidence for MAF governing a wider range of developmental programs than previously appreciated, and describe a novel instance of protein dosage effect severely perturbing development.
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- 2015
17. CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder
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Christine Klein, Szymon Ziętkiewicz, Thomas Meitinger, Ewa Pronicka, Tim M. Strom, Clara D.M. van Karnebeek, Saskia B. Wortmann, Ron A. Wevers, Frédéric M. Vaz, Tobias B. Haack, Felix Distelmaier, Elzbieta Chrusciel, Thomas Lücke, Søren W. Gersting, Joop H. Jansen, Christelle Golzio, M. Estela Rubio-Gozalbo, Nicholas Katsanis, Michèl A.A.P. Willemsen, Joy Yaplito-Lee, Katrin Õunap, Riina Zordania, Richard J. Rodenburg, Radek Szklarczyk, Maria Kousi, Yolanda Lillquist, Johannes N. Spelbrink, Holger Prokisch, G. Herma Renkema, Hans van Bokhoven, Arjan P.M. de Brouwer, Aleksandar Rakovic, Mia L. Pras-Raves, Ania C. Muntau, Rafał Płoski, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Laboratory Genetic Metabolic Diseases, RS: GROW - Developmental Biology, RS: GROW - R4 - Reproductive and Perinatal Medicine, and MUMC+: DA KG Lab Centraal Lab (9)
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Neutropenia ,Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2] ,Molecular Sequence Data ,Encephalopathy ,Biology ,Polymorphism, Single Nucleotide ,Cataract ,Article ,Sarcoplasmic Reticulum Calcium-Transporting ATPases ,03 medical and health sciences ,0302 clinical medicine ,Atrophy ,Intellectual Disability ,Genetics ,medicine ,Animals ,Humans ,Abnormalities, Multiple ,Exome ,Genetics(clinical) ,Congenital Neutropenia ,Zebrafish ,Genetics (clinical) ,Exome sequencing ,030304 developmental biology ,Adenosine Triphosphatases ,Cerebral atrophy ,0303 health sciences ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,Movement Disorders ,Base Sequence ,Brain ,Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6] ,Endopeptidase Clp ,Sequence Analysis, DNA ,3-Methylglutaconic Aciduria ,Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] ,medicine.disease ,HAX1 ,CLPB ,Metabolism, Inborn Errors ,030217 neurology & neurosurgery - Abstract
Item does not contain fulltext We studied a group of individuals with elevated urinary excretion of 3-methylglutaconic acid, neutropenia that can develop into leukemia, a neurological phenotype ranging from nonprogressive intellectual disability to a prenatal encephalopathy with progressive brain atrophy, movement disorder, cataracts, and early death. Exome sequencing of two unrelated individuals and subsequent Sanger sequencing of 16 individuals with an overlapping phenotype identified a total of 14 rare, predicted deleterious alleles in CLPB in 14 individuals from 9 unrelated families. CLPB encodes caseinolytic peptidase B homolog ClpB, a member of the AAA+ protein family. To evaluate the relevance of CLPB in the pathogenesis of this syndrome, we developed a zebrafish model and an in vitro assay to measure ATPase activity. Suppression of clpb in zebrafish embryos induced a central nervous system phenotype that was consistent with cerebellar and cerebral atrophy that could be rescued by wild-type, but not mutant, human CLPB mRNA. Consistent with these data, the loss-of-function effect of one of the identified variants (c.1222A>G [p.Arg408Gly]) was supported further by in vitro evidence with the mutant peptides abolishing ATPase function. Additionally, we show that CLPB interacts biochemically with ATP2A2, known to be involved in apoptotic processes in severe congenital neutropenia (SCN) 3 (Kostmann disease [caused by HAX1 mutations]). Taken together, mutations in CLPB define a syndrome with intellectual disability, congenital neutropenia, progressive brain atrophy, movement disorder, cataracts, and 3-methylglutaconic aciduria.
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- 2015
18. RAC1 Missense Mutations in Developmental Disorders with Diverse Phenotypes
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Nicholas Katsanis, Katie Clarkson, Grazia M.S. Mancini, Margot R.F. Reijnders, Ken Corning, Rolph Pfundt, Han G. Brunner, Carlo Marcelis, Thomas H. Millard, Nurhuda Mohamad Ansor, Ronald D. Cohn, Wyatt W. Yue, Siddharth Banka, Shehla Mohammed, Perciliz L. Tan, Jill Clayton-Smith, David Chitayat, Julie R. Jones, Wayne W.K. Lam, Maian Roifman, Maria Kousi, Klinische Genetica, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA Klinische Genetica (5), and Clinical Genetics
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Male ,rac1 GTP-Binding Protein ,0301 basic medicine ,Microcephaly ,Embryo, Nonmammalian ,INTELLECTUAL DISABILITY ,Developmental Disabilities ,VARIANTS ,Mice ,0302 clinical medicine ,Missense mutation ,Child ,Zebrafish ,Genetics (clinical) ,Genetics ,Brain Diseases ,biology ,RHO GTPASES ,CDC42 ,Phenotype ,Pedigree ,FAMILY ,Child, Preschool ,SURVIVAL ,GROWTH ,Female ,Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] ,EXPRESSION ,Adolescent ,In silico ,Mutation, Missense ,Context (language use) ,03 medical and health sciences ,Report ,medicine ,Animals ,Humans ,Amino Acid Sequence ,Allele ,Gene ,SPECTRUM ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,Infant ,biology.organism_classification ,medicine.disease ,030104 developmental biology ,030217 neurology & neurosurgery ,SYSTEM - Abstract
Contains fulltext : 177246.pdf (Publisher’s version ) (Open Access) RAC1 is a widely studied Rho GTPase, a class of molecules that modulate numerous cellular functions essential for normal development. RAC1 is highly conserved across species and is under strict mutational constraint. We report seven individuals with distinct de novo missense RAC1 mutations and varying degrees of developmental delay, brain malformations, and additional phenotypes. Four individuals, each harboring one of c.53G>A (p.Cys18Tyr), c.116A>G (p.Asn39Ser), c.218C>T (p.Pro73Leu), and c.470G>A (p.Cys157Tyr) variants, were microcephalic, with head circumferences between -2.5 to -5 SD. In contrast, two individuals with c.151G>A (p.Val51Met) and c.151G>C (p.Val51Leu) alleles were macrocephalic with head circumferences of +4.16 and +4.5 SD. One individual harboring a c.190T>G (p.Tyr64Asp) allele had head circumference in the normal range. Collectively, we observed an extraordinary spread of approximately 10 SD of head circumferences orchestrated by distinct mutations in the same gene. In silico modeling, mouse fibroblasts spreading assays, and in vivo overexpression assays using zebrafish as a surrogate model demonstrated that the p.Cys18Tyr and p.Asn39Ser RAC1 variants function as dominant-negative alleles and result in microcephaly, reduced neuronal proliferation, and cerebellar abnormalities in vivo. Conversely, the p.Tyr64Asp substitution is constitutively active. The remaining mutations are probably weakly dominant negative or their effects are context dependent. These findings highlight the importance of RAC1 in neuronal development. Along with TRIO and HACE1, a sub-category of rare developmental disorders is emerging with RAC1 as the central player. We show that ultra-rare disorders caused by private, non-recurrent missense mutations that result in varying phenotypes are challenging to dissect, but can be delineated through focused international collaboration.
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- 2017
19. ZNHIT3 is defective in PEHO syndrome, a severe encephalopathy with cerebellar granule neuron loss
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Anna-Elina Lehesjoki, Maria Kousi, Mikko Muona, Melody P. Lun, Saara Tegelberg, Jorma J. Palvimo, Yawei J. Yang, Eija Siintola, Nicholas Katsanis, Anna-Kaisa Anttonen, Tiina Jääskeläinen, Maria K. Lehtinen, Outi Kopra, Tuula Lönnqvist, Tarja Joensuu, Anni Laari, Leena Valanne, Anders Paetau, Helena Pihko, Eveliina Jakkula, Johanna Hästbacka, Mirja Somer, Department of Medical and Clinical Genetics, Neuroscience Center, Anna-Elina Lehesjoki / Principal Investigator, University of Helsinki, Research Programme for Molecular Neurology, Research Programs Unit, Medicum, Doctoral Programme in Biomedicine, Institute for Molecular Medicine Finland, HUS Children and Adolescents, Clinicum, Children's Hospital, Lastenneurologian yksikkö, Department of Diagnostics and Therapeutics, HUS Medical Imaging Center, HUSLAB, and Department of Pathology
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0301 basic medicine ,Cerebellum ,ZNHIT3 ,Brain Edema ,progressive encephalopathy ,3124 Neurology and psychiatry ,Mice ,0302 clinical medicine ,Mutant protein ,Cell Movement ,Missense mutation ,PEHO syndrome ,Exome ,Exome sequencing ,Zebrafish ,Zinc finger ,Gene Editing ,Neurons ,COACTIVATOR ,Nuclear Proteins ,Neurodegenerative Diseases ,THYROID-HORMONE RECEPTOR ,SYNDROME PROGRESSIVE ENCEPHALOPATHY ,Cell biology ,medicine.anatomical_structure ,DIFFERENTIATION ,Gene Knockdown Techniques ,Microcephaly ,Cerebellar atrophy ,Spasms, Infantile ,HYPSARRHYTHMIA ,cerebellum ,Cell Survival ,Mutation, Missense ,Biology ,SEVERE IMPAIRMENT ,03 medical and health sciences ,OXIDATIVE-STRESS ,HYPOARRHYTHMIA ,medicine ,Animals ,Humans ,COP9 Signalosome Complex ,OPTIC ATROPHY ,3112 Neurosciences ,Sequence Analysis, DNA ,EDEMA ,Granule cell ,medicine.disease ,030104 developmental biology ,Neurology (clinical) ,030217 neurology & neurosurgery ,Transcription Factors - Abstract
Progressive encephalopathy with oedema, hypsarrhythmia, and optic atrophy (PEHO) syndrome is an early childhood onset, severe autosomal recessive encephalopathy characterized by extreme cerebellar atrophy due to almost total granule neuron loss. By combining homozygosity mapping in Finnish families with Sanger sequencing of positional candidate genes and with exome sequencing a homozygous missense substitution of leucine for serine at codon 31 in ZNHIT3 was identified as the primary cause of PEHO syndrome. ZNHIT3 encodes a nuclear zinc finger protein previously implicated in transcriptional regulation and in small nucleolar ribonucleoprotein particle assembly and thus possibly to pre-ribosomal RNA processing. The identified mutation affects a highly conserved amino acid residue in the zinc finger domain of ZNHIT3. Both knockdown and genome editing of znhit3 in zebrafish embryos recapitulate the patients' cerebellar defects, microcephaly and oedema. These phenotypes are rescued by wild-type, but not mutant human ZNHIT3 mRNA, suggesting that the patient missense substitution causes disease through a loss-of-function mechanism. Transfection of cell lines with ZNHIT3 expression vectors showed that the PEHO syndrome mutant protein is unstable. Immunohistochemical analysis of mouse cerebellar tissue demonstrated ZNHIT3 to be expressed in proliferating granule cell precursors, in proliferating and post-mitotic granule cells, and in Purkinje cells. Knockdown of Znhit3 in cultured mouse granule neurons and ex vivo cerebellar slices indicate that ZNHIT3 is indispensable for granule neuron survival and migration, consistent with the zebrafish findings and patient neuropathology. These results suggest that loss-of-function of a nuclear regulator protein underlies PEHO syndrome and imply that establishment of its spatiotemporal interaction targets will be the basis for developing therapeutic approaches and for improved understanding of cerebellar development.
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- 2017
20. Decreased Aerobic Capacity in ANO5-Muscular Dystrophy
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Tapani Salmi, Ibrahim Mahjneh, Mari Auranen, Tiina Muurinen, Ann-Liz Träskelin, Anna-Elina Lehesjoki, Anders Paetau, Mervi Löfberg, Maria Kousi, Emil Ylikallio, Päivi Piirilä, Sari Kiuru-Enari, Antti Lamminen, HUS Neurocenter, Research Programme for Molecular Neurology, Research Programs Unit, Clinicum, Neurologian yksikkö, Department of Neurosciences, HUS Medical Imaging Center, Department of Diagnostics and Therapeutics, Kliinisen neurofysiologian yksikkö, HUSLAB, Medicum, Department of Pathology, Neuroscience Center, and Anna-Elina Lehesjoki / Principal Investigator
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Adult ,Male ,0301 basic medicine ,Heterozygote ,education ,Anoctamins ,Physiology ,Electromyography ,Biology ,Compound heterozygosity ,03 medical and health sciences ,Oxygen Consumption ,0302 clinical medicine ,medicine ,Humans ,Aerobic exercise ,Muscular dystrophy ,Muscle, Skeletal ,Exercise ,Finland ,Aerobic capacity ,Muscle biopsy ,medicine.diagnostic_test ,Homozygote ,Case-control study ,1184 Genetics, developmental biology, physiology ,Heterozygote advantage ,Middle Aged ,medicine.disease ,Magnetic Resonance Imaging ,3. Good health ,030104 developmental biology ,Muscular Dystrophies, Limb-Girdle ,Neurology ,Case-Control Studies ,Exercise Test ,Female ,Neurology (clinical) ,030217 neurology & neurosurgery - Abstract
Background Anoctaminopathies are muscle diseases caused by recessive mutations in the ANO5 gene. The effects of anoctaminopathy on oxidative capacity have not previously been studied in a controlled setting. Objective To characterize oxidative capacity in a clinically and genetically well-defined series of patients with anoctaminopathy. Methods We sequenced the ANO5 gene in 111 Finnish patients with suspected LGMD2. Patients with positive findings underwent close clinical examination, including electromyography, muscle MRI, and, in selected cases, muscle biopsy. Oxidative capacity was analyzed using spiroergometry and compared to age-matched healthy controls. Results We characterized 12 newly identified and 2 previously identified patients with ANO5 mutations from 11 families. Our material was genetically homogeneous with most patients homozygous for the Finnish founder variant c.2272C>T (p.Arg758Cys). In one family, we found a novel p.Met470Arg variant compound heterozygous with p.Arg758Cys. Lower limb muscle MRI revealed progressive fatty degeneration of specific posterior compartment muscles. Patients' spiroergometric profiles showed that anoctaminopathy significantly impaired oxidative capacity with increasing ventilation. Conclusions Our findings support earlier reports that anoctaminopathy progresses slowly and demonstrate that the disease impairs the capacity for aerobic exercise.
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- 2016
21. The Genetic Basis of Hydrocephalus
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Maria Kousi and Nicholas Katsanis
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0301 basic medicine ,Biology ,03 medical and health sciences ,symbols.namesake ,medicine ,Animals ,Humans ,Genetic Predisposition to Disease ,Expressivity (genetics) ,Allele ,Cerebrospinal Fluid ,Genetics ,General Neuroscience ,Inheritance (genetic algorithm) ,Brain ,medicine.disease ,Penetrance ,Hydrocephalus ,030104 developmental biology ,Phenotype ,Aqueductal stenosis ,Mutation ,Mendelian inheritance ,symbols ,Identification (biology) ,Neuroscience - Abstract
Studies of syndromic hydrocephalus have led to the identification of >100 causative genes. Even though this work has illuminated numerous pathways associated with hydrocephalus, it has also highlighted the fact that the genetics underlying this phenotype are more complex than anticipated originally. Mendelian forms of hydrocephalus account for a small fraction of the genetic burden, with clear evidence of background-dependent effects of alleles on penetrance and expressivity of driver mutations in key developmental and homeostatic pathways. Here, we synthesize the currently implicated genes and inheritance paradigms underlying hydrocephalus, grouping causal loci into functional modules that affect discrete, albeit partially overlapping, cellular processes. These in turn have the potential to both inform pathomechanism and assist in the rational molecular classification of a clinically heterogeneous phenotype. Finally, we discuss conceptual methods that can lead to enhanced gene identification and dissection of disease basis, knowledge that will potentially form a foundation for the design of future therapeutics.
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- 2016
22. Novel mutations consolidateKCTD7as a progressive myoclonus epilepsy gene
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Hannu Kalimo, Angela Schulz, Maria Kousi, Liisa Myllykangas, Anna-Elina Lehesjoki, Erik Riesch, Aarno Palotie, Füsun Alehan, Stella Calafato, Verneri Anttila, Outi Kopra, Johannes R Lemke, Eveliina Jakkula, Michael Alber, Meral Topçu, Sarenur Gökben, and Çocuk Sağlığı ve Hastalıkları
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Potassium Channels ,Ataxia ,Turkey ,KCTD7 ,Blotting, Western ,Intracellular Space ,Single-nucleotide polymorphism ,Progressive myoclonus epilepsy ,Biology ,Polymorphism, Single Nucleotide ,Article ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Genetics ,medicine ,Animals ,Humans ,Missense mutation ,Cells, Cultured ,Genetics (clinical) ,030304 developmental biology ,Brain Chemistry ,Genetics & Heredity ,0303 health sciences ,Genetic heterogeneity ,Homozygote ,Chromosome Mapping ,Sequence Analysis, DNA ,Myoclonic Epilepsies, Progressive ,medicine.disease ,Disease gene identification ,Pedigree ,3. Good health ,Phenotype ,Microscopy, Fluorescence ,Mutation ,medicine.symptom ,Myoclonus ,030217 neurology & neurosurgery - Abstract
Background The progressive myoclonus epilepsies (PMEs) comprise a group of clinically and genetically heterogeneous disorders characterised by myoclonus, epilepsy, and neurological deterioration. This study aimed to identify the underlying gene(s) in childhood onset PME patients with unknown molecular genetic background. Methods Homozygosity mapping was applied on genome-wide single nucleotide polymorphism data of 18 Turkish patients. The potassium channel tetramerisation domain-containing 7 ( KCTD7 ) gene, previously associated with PME in a single inbred family, was screened for mutations. The spatiotemporal expression of KCTD7 was assessed in cellular cultures and mouse brain tissue. Results Overlapping homozygosity in 8/18 patients defined a 1.5 Mb segment on 7q11.21 as the major candidate locus. Screening of the positional candidate gene KCTD7 revealed homozygous missense mutations in two of the eight cases. Screening of KCTD7 in a further 132 PME patients revealed four additional mutations (two missense, one in-frame deletion, and one frameshift-causing) in five families. Eight patients presented with myoclonus and epilepsy and one with ataxia, the mean age of onset being 19 months. Within 2 years after onset, progressive loss of mental and motor skills ensued leading to severe dementia and motor handicap. KCTD7 showed cytosolic localisation and predominant neuronal expression, with widespread expression throughout the brain. None of three polypeptides carrying patient missense mutations affected the subcellular distribution of KCTD7. Discussion These data confirm the causality of KCTD7 defects in PME, and imply that KCTD7 mutation screening should be considered in PME patients with onset around 2 years of age followed by rapid mental and motor deterioration.
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- 2012
23. Update of the mutation spectrum and clinical correlations of over 360 mutations in eight genes that underlie the neuronal ceroid lipofuscinoses
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Maria Kousi, Anna-Elina Lehesjoki, and Sara E. Mole
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Adult ,Batten disease ,Adolescent ,Genotype ,Blindness ,medicine.disease_cause ,Severity of Illness Index ,03 medical and health sciences ,0302 clinical medicine ,Neuronal Ceroid-Lipofuscinoses ,Genetics ,medicine ,Humans ,Palmitoyl protein thioesterase ,Genetics (clinical) ,030304 developmental biology ,0303 health sciences ,Mutation ,Epilepsy ,Membrane Glycoproteins ,Tripeptidyl-Peptidase 1 ,biology ,Mortality, Premature ,Genetic heterogeneity ,Jansky–Bielschowsky disease ,Genetic Variation ,Infant ,PPT1 ,Exons ,medicine.disease ,Tripeptidyl peptidase I ,Introns ,3. Good health ,Phenotype ,CLN8 ,biology.protein ,030217 neurology & neurosurgery ,Molecular Chaperones - Abstract
The neuronal ceroid lipofuscinoses (NCLs) are clinically and genetically heterogeneous neurodegenerative disorders. Most are autosomal recessively inherited. Clinical features include a variable age of onset, motor and mental decline, epilepsy, visual loss, and premature death. Mutations in eight genes (PPT1/CLN1, TPP1/CLN2, CLN3, CLN5, CLN6, MFSD8/CLN7, CLN8) have been identified and several more are predicted to exist, including two provisionally named CLN4 and CLN9. Despite excessive in vitro and in vivo studies, the precise functions of the NCL proteins and the disease mechanisms remain elusive. To date 365 NCL-causing mutations are known, with 91 novel disease-causing mutations reported. These are reviewed with an emphasis on their complex correlation to phenotypes. Different mutations within the NCL spectrum can cause variable disease severity. The NCLs exemplify both phenotypic convergence or mimicry and phenotypic divergence. For example, mutations in CLN5, CLN6, MFSD8, or CLN8 can underlie the clinically similar late infantile variant NCL disease. Phenotypic divergence is exemplified by different CLN8 mutations giving rise to two very different diseases, the mild CLN8 disease, EPMR (progressive epilepsy with mental retardation), and the more severe CLN8 disease, late infantile variant. The increase in the genetic understanding of the NCLs has led to improved diagnostic approaches, and the recent proposal of a new nomenclature.
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- 2011
24. Suggestive evidence for a new locus for epilepsy with heterogeneous phenotypes on chromosome 17q
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Matti Koivikko, Reijo Laaksonen, Maria Kousi, Lyne Chahine, Malgorzata Labuda, Massimo Pandolfo, Asta Laiho, Kalle O.J. Simola, Auli Siren, Anne Polvi, Juhani T. Soini, Anna-Elina Lehesjoki, Eva Andermann, Anna-Kaisa Anttonen, Sarah Bourgoin, and Kari Hirvonen
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Adult ,Male ,Candidate gene ,Adolescent ,Genotype ,DNA Mutational Analysis ,Locus (genetics) ,Biology ,Ion Channels ,Childhood absence epilepsy ,Genetic linkage ,Febrile seizure ,medicine ,Humans ,Copy-number variation ,Child ,Aged ,Oligonucleotide Array Sequence Analysis ,Family Health ,Genetics ,Epilepsy ,Gene Expression Profiling ,Chromosome Mapping ,Middle Aged ,medicine.disease ,Penetrance ,Phenotype ,Neurology ,Child, Preschool ,Mutation ,Female ,Neurology (clinical) ,Lod Score ,Chromosomes, Human, Pair 17 ,Comparative genomic hybridization - Abstract
Summary Purpose To characterize the clinical features and molecular genetic background in a family with various epilepsy phenotypes including febrile seizures, childhood absence epilepsy, and possible temporal lobe epilepsy. Methods Clinical data were collected. DNA and RNA were extracted from peripheral blood. A genome-wide microsatellite marker scan was performed and regions with a multipoint location score ≥1.5 were fine mapped. Functional candidate genes identified from databases and by comparing gene expression profiles of genes between affected and unaffected individuals were sequenced. Copy number variation was evaluated with array-based comparative genomic hybridization. Results The seizure phenotype was benign. Inheritance was consistent with an autosomal dominant model and reduced penetrance. The highest two-point LOD score of 2.8 was identified at marker D17S1606 in a 37cM interval on chromosome 17q12-q24. Loci on 5q11.2 and on 18p11-q11, showed LOD scores ≥1.5 after fine mapping. Sequencing of nine ion-channel genes and two ( RPIP8 and SLC25A39 ) differentially expressed genes from 17q12-q24, as well as IMPA2 from 18p11-q11 did not reveal a pathogenic alteration. No clinically relevant copy number variation was identified. Conclusions Our findings suggest complex inheritance of seizure susceptibility in the family with contribution from three loci, including a possible new locus on chromosome 17q. The underlying molecular defects remain unknown.
- Published
- 2010
25. Mutations in CLN7/MFSD8 are a common cause of variant late-infantile neuronal ceroid lipofuscinosis
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Meral Topçu, Sarenur Gökben, Milan Elleder, Sara E. Mole, Berge A. Minassian, Hana Vlaskova, Julie Turnbull, Eija Siintola, Anna-Elina Lehesjoki, Deniz Yüksel, Maria Kousi, Lenka Dvorakova, Ege Üniversitesi, and Çocuk Sağlığı ve Hastalıkları
- Subjects
Male ,Batten disease ,DNA Mutational Analysis ,Molecular Sequence Data ,Biology ,medicine.disease_cause ,03 medical and health sciences ,0302 clinical medicine ,Neuronal Ceroid-Lipofuscinoses ,medicine ,Humans ,Age of Onset ,Child ,030304 developmental biology ,Genetics ,0303 health sciences ,Mutation ,Base Sequence ,Tripeptidyl-Peptidase 1 ,Genetic heterogeneity ,Infant ,Membrane Transport Proteins ,PPT1 ,MFSD8 ,CLN7 ,mutations ,medicine.disease ,3. Good health ,Haplotypes ,CLN8 ,Child, Preschool ,Female ,Neuronal ceroid lipofuscinosis ,Neurosciences & Neurology ,neuronal ceroid lipofuscinosis ,Neurology (clinical) ,Age of onset ,030217 neurology & neurosurgery ,Founder effect - Abstract
WOS: 000264889000024, PubMed ID: 19201763, The neuronal ceroid lipofuscinoses (NCLs), the most common neurodegenerative disorders of childhood, are characterized by the accumulation of autofluorescent storage material mainly in neurons. Although clinically rather uniform, variant late-infantile onset NCL (vLINCL) is genetically heterogeneous with four major underlying genes identified so far. We evaluated the genetic background underlying vLINCL in 119 patients, and specifically analysed the recently reported CLN7/MFSD8 gene for mutations in 80 patients. Clinical data were collected from the CLN7/MFSD8 mutation positive patients. Eight novel CLN7/MFSD8 mutations and seven novel mutations in the CLN1/PPT1, CLN2/TPP1, CLN5, CLN6 and CLN8 genes were identified in patients of various ethnic origins. A significant group of Roma patients originating from the former Czechoslovakia was shown to bear the c.881CA (p.Thr294Lys) mutation in CLN7/MFSD8, possibly due to a founder effect. With one exception, the CLN7/MFSD8 mutation positive patients present a phenotype indistinguishable from the other vLINCL forms. In one patient with an in-frame amino acid substitution mutation in CLN7/MFSD8, the disease onset was later and the disease course less aggressive than in variant late-infantile NCL. Our findings raise the total number of CLN7/MFSD8 mutations to 14 with the majority of families having private mutations. Our study confirms that CLN7/MFSD8 defects are not restricted to the Turkish population, as initially anticipated, but are a relatively common cause of NCL in different populations. CLN7/MFSD8 should be considered a diagnostic alternative not only in variant late-infantile but also later onset NCL forms with a more protracted disease course. A significant number of NCL patients in Turkey exist, in which the underlying genetic defect remains to be determined., Center of Excellence in Complex Disease Genetics of the Academy of FinlandAcademy of Finland; Folkhalsan Research Foundation; Institute of Inherited Metabolic Disorders support [MSM 0021620806]; Ministry of Health of the Czech Republic grantMinistry of Health, Czech Republic [NR/8351-3]; Wellcome TrustWellcome Trust [054606]; Batten Disease Support and Research Association; Helsinki Biomedical Graduate School, We thank the families that participated in this study, as well as Marianne Rohrbach, Stacey Hewson, Eva Kostalova, Gul Serdaroglu, Larisa Stolnaja, Claudia Kitzmuller, Ahmed Mohamed and Teija-Tuulia Toivonen for their contribution. This study was supported by the Center of Excellence in Complex Disease Genetics of the Academy of Finland, the Folkhalsan Research Foundation, the Institute of Inherited Metabolic Disorders support (project MSM 0021620806), the Ministry of Health of the Czech Republic grant (NR/8351-3), the Wellcome Trust (054606) and the Batten Disease Support and Research Association. M. K. is fellow of the Helsinki Biomedical Graduate School. B. A. M. holds a Canada Research Chair in Pediatric Neurogenetics.
- Published
- 2009
26. Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy
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Jason R. Willer, Matthew N. Bainbridge, James R. Lupski, Igor Pediaditrakis, Marjorie Withers, Nicholas Katsanis, Michel Koenig, Eric Boerwinkle, Tomasz Gambin, Donna M. Muzny, Tamar Harel, Ludmila Francescatto, Pamela J. Reitnauer, Laurie B. Griffin, Yesim Parman, Wojciech Wiszniewski, Davut Pehlivan, Richard A. Gibbs, Kim Lawson, Maria Kousi, Yuji Okamoto, Anne Slavotinek, Burcak Ozes, Michael E. Shy, Thomas O. Crawford, Ender Karaca, Meryem Tuba Goksungur, Shalini N. Jhangiani, Esra Battaloglu, Brittany N. Flores, Claudia Gonzaga-Jauregui, Anthony Antonellis, Pedro Mancias, Onder Us, Department of Pediatrics, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC)-School of Medicine, University of Michigan [Ann Arbor], University of Michigan System, Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Human Genome Sequencing Center, Baylor College of Medicine, Baylor College of Medicine (BCM), Baylor University-Baylor University, Department of Molecular and Human Genetics (Baylor College of Medicine), and Baylor College of Medecine
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Male ,Serine C-Palmitoyltransferase ,Penetrance ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,Biology ,Bioinformatics ,medicine.disease_cause ,Myelin P2 Protein ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,0302 clinical medicine ,Suppression, Genetic ,Charcot-Marie-Tooth Disease ,Genetic variation ,medicine ,Animals ,Humans ,Exome ,lcsh:QH301-705.5 ,Zebrafish ,030304 developmental biology ,Genetics ,0303 health sciences ,Mutation ,Genetic heterogeneity ,Genetic Variation ,Peripheral Nervous System Diseases ,HSP40 Heat-Shock Proteins ,medicine.disease ,Phenotype ,3. Good health ,Genetic load ,Pedigree ,Peripheral neuropathy ,lcsh:Biology (General) ,Female ,Genetic Load ,030217 neurology & neurosurgery - Abstract
International audience; Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous distal symmetric polyneuropathy. Whole-exome sequencing (WES) of 40 individuals from 37 unrelated families with CMT-like peripheral neuropathy refractory to molecular diagnosis identified apparent causal mutations in ∼ 45% (17/37) of families. Three candidate disease genes are proposed, supported by a combination of genetic and in vivo studies. Aggregate analysis of mutation data revealed a significantly increased number of rare variants across 58 neuropathy-associated genes in subjects versus controls, confirmed in a second ethnically discrete neuropathy cohort, suggesting that mutation burden potentially contributes to phenotypic variability. Neuropathy genes shown to have highly penetrant Mendelizing variants (HPMVs) and implicated by burden in families were shown to interact genetically in a zebrafish assay exacerbating the phenotype established by the suppression of single genes. Our findings suggest that the combinatorial effect of rare variants contributes to disease burden and variable expressivity.
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- 2015
27. TAF1 Variants are associated with dysmorphic features, intellectual disability, and neurological manifestations
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Maria Kousi, Kay Metcalfe, Laura T. Jiménez-Barrón, Christopher Smith, Jane L. Schuette, Jean Baptiste Rivière, Sara Ellingwood, Erica E. Davis, Sander Stegmann, Alfonso Caro-Llopis, Maria Tzetis, David Mittelman, Sophia Kitsiou-Tzeli, Edith H. Wang, Vera M. Kalscheuer, A. Micheil Innes, Konstantina Kosma, Jillian S. Parboosingh, P.Y. Billie Au, Kristin G. Monaghan, Carlos E. Prada, Rosemarie Smith, Laurence Faivre, Sandra Monfort, Alan F. Rope, Jonathan Crain, Mónica Roselló, Yiyang Wu, Reid J. Robison, Jeffrey Swensen, Francisco Martínez, Max Dorfel, Carmen Orellana, Robert B. Hufnagel, Gareth Highnam, Kai Wang, Sungjin Moon, Tjitske Kleefstra, Edward Yang, Nicholas Katsanis, Sandra Ospina, Nicolette S. den Hollander, Catherine E. Keegan, Gholson J. Lyon, Jason O'Rawe, Silvestre Oltra, Han Fang, and Agathe Roubertie
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Proband ,Male ,Gene Mutation ,Neurologic Features ,Developmental Disabilities ,Intellectual Impairment ,Inheritance Patterns ,Intergluteal Crease ,Tata-Binding Protein Associated Factors ,E-Box Elements ,Gene Duplication ,Recessive Inheritance ,Pathology ,Genetics(clinical) ,Child ,Gene knockdown ,Clinical Article ,Genetic Screening ,Neurodegeneration ,Pedigree ,developmental delay ,Dystonia ,Child, Preschool ,Priority Journal ,dystonia ,Transcription Factor Iid ,Human ,Disease Model ,Article ,Rna Sequence ,Unclassified Drug ,Histone Acetyltransferase ,Intellectual Disability ,Genetics ,Humans ,Family ,Degenerative Disease ,TATA-Binding Protein Associated Factors ,Face Dysmorphia ,Phenotypic Variation ,School Child ,Animal ,Infant ,Transcription Factor Tfiid ,facial dysmorphology ,medicine.disease ,Tata-Binding Protein Associated Factor 25 Kda ,Nerve Degeneration ,Mutation ,intergluteal crease ,Single Nucleotide Polymorphism ,Transcription Factor TFIID ,Developmental Disorder ,Transcription Factor ,Facial Dysmorphology ,Zebra Fish ,Clinical Evaluation ,Family Assessment ,Abnormal Gait ,Intellectual disability ,neurologic features ,Down Regulation ,Global developmental delay ,Preschool Child ,Zebrafish ,Tata Binding Protein Associated Factor ,Genetics (clinical) ,Histone Acetyltransferases ,Inheritance ,Neurodegenerative Diseases ,Neurologic Disease ,Phenotype ,intellectual disability ,Muscle Hypotonia ,transcription ,Transcription ,Genetic Association ,Signal Transduction ,Adolescent ,E Box Element ,Biology ,Enfermedades genéticas en los niños ,Young Adult ,Report ,medicine ,Genetic Disorder ,TAF1 ,Taf1 ,Animals ,Gene ,Developmental Delay ,abnormal gait ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,Protein ,Facies ,Ginecología & otras especialidades médicas ,Clinical Feature ,biology.organism_classification ,Disease Models, Animal ,Metabolism ,E Box Protein ,Gene Expression Regulation ,Clinical Assessment ,Anormalidades de los cromosomas sexuales en niños - Abstract
Contains fulltext : 152777.pdf (Publisher’s version ) (Open Access) We describe an X-linked genetic syndrome associated with mutations in TAF1 and manifesting with global developmental delay, intellectual disability (ID), characteristic facial dysmorphology, generalized hypotonia, and variable neurologic features, all in male individuals. Simultaneous studies using diverse strategies led to the identification of nine families with overlapping clinical presentations and affected by de novo or maternally inherited single-nucleotide changes. Two additional families harboring large duplications involving TAF1 were also found to share phenotypic overlap with the probands harboring single-nucleotide changes, but they also demonstrated a severe neurodegeneration phenotype. Functional analysis with RNA-seq for one of the families suggested that the phenotype is associated with downregulation of a set of genes notably enriched with genes regulated by E-box proteins. In addition, knockdown and mutant studies of this gene in zebrafish have shown a quantifiable, albeit small, effect on a neuronal phenotype. Our results suggest that mutations in TAF1 play a critical role in the development of this X-linked ID syndrome.
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- 2015
28. Missense mutations in TENM4, a regulator of axon guidance and central myelination, cause essential tremor
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Xavier Estivill, Jordi Clarimón, Pau Pastor, Ruth Chiquet-Ehrismann, Daniela Kenzelmann Broz, Maria Kousi, Hyun Hor, Félix Javier Jiménez-Jiménez, Sara Ortega-Cubero, Stephan Ossowski, Luca Bartesaghi, Ludmila Francescatto, Elena García-Martín, Alexandre Gironell, Roman Chrast, María José Martí, Hortensia Alonso-Navarro, F. Coria, Oswaldo Lorenzo-Betancor, Charlotte N. Hor, Jaume Kulisevsky, Alberto Lleó, José A. G. Agúndez, Nicholas Katsanis, and Oliver Drechsel
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Adult ,Male ,Essential Tremor ,Population ,DNA Mutational Analysis ,Mutation, Missense ,Biology ,Dominant-Negative Mutation ,medicine.disease_cause ,Mice ,Young Adult ,Genetics ,medicine ,Missense mutation ,Animals ,Humans ,Exome ,education ,Molecular Biology ,Zebrafish ,Genetics (clinical) ,Exome sequencing ,education.field_of_study ,Mutation ,Membrane Glycoproteins ,General Medicine ,Articles ,Middle Aged ,biology.organism_classification ,Phenotype ,Axons ,3. Good health ,Pedigree ,Oligodendroglia ,Protein Transport ,Axon guidance ,Female - Abstract
Essential tremor (ET) is a common movement disorder with an estimated prevalence of 5% of the population aged over 65 years. In spite of intensive efforts, the genetic architecture of ET remains unknown. We used a combination of whole-exome sequencing and targeted resequencing in three ET families. In vitro and in vivo experiments in oligodendrocyte precursor cells and zebrafish were performed to test our findings. Whole-exome sequencing revealed a missense mutation in TENM4 segregating in an autosomal-dominant fashion in an ET family. Subsequent targeted resequencing of TENM4 led to the discovery of two novel missense mutations. Not only did these two mutations segregate with ET in two additional families, but we also observed significant over transmission of pathogenic TENM4 alleles across the three families. Consistent with a dominant mode of inheritance, in vitro analysis in oligodendrocyte precursor cells showed that mutant proteins mislocalize. Finally, expression of human mRNA harboring any of three patient mutations in zebrafish embryos induced defects in axon guidance, confirming a dominant-negative mode of action for these mutations. Our genetic and functional data, which is corroborated by the existence of a Tenm4 knockout mouse displaying an ET phenotype, implicates TENM4 in ET. Together with previous studies of TENM4 in model organisms, our studies intimate that processes regulating myelination in the central nervous system and axon guidance might be significant contributors to the genetic burden of this disorder.
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- 2015
29. Activating mutations in STIM1 and ORAI1 cause overlapping syndromes of tubular myopathy and congenital miosis
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Thomas Lehmann, Graham B. Wiley, Nortina Shahrizaila, Patrick M. Gaffney, E-Ching Ong, Mohnish Suri, Klaas J. Wierenga, Nicholas Katsanis, Maria Kousi, Leonidas Tsiokas, Vasyl Nesin, and David Nicholl
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Miosis ,medicine.medical_specialty ,Patch-Clamp Techniques ,ORAI1 Protein ,Migraine Disorders ,Molecular Sequence Data ,Erythrocytes, Abnormal ,Biology ,medicine.disease_cause ,Dyslexia ,Internal medicine ,medicine ,Animals ,Humans ,Congenital miosis ,Calcium Signaling ,Stromal Interaction Molecule 1 ,Myopathy ,Child ,Zebrafish ,Calcium signaling ,DNA Primers ,Mutation ,Multidisciplinary ,Base Sequence ,ORAI1 ,Ichthyosis ,Membrane Proteins ,STIM1 ,Sequence Analysis, DNA ,Biological Sciences ,medicine.disease ,Neoplasm Proteins ,Pedigree ,Bleeding diathesis ,Endocrinology ,Muscle Fatigue ,Cancer research ,Mutagenesis, Site-Directed ,Female ,Blood Platelet Disorders ,Calcium Channels ,medicine.symptom ,Spleen ,Myopathies, Structural, Congenital - Abstract
Signaling through the store-operated Ca(2+) release-activated Ca(2+) (CRAC) channel regulates critical cellular functions, including gene expression, cell growth and differentiation, and Ca(2+) homeostasis. Loss-of-function mutations in the CRAC channel pore-forming protein ORAI1 or the Ca(2+) sensing protein stromal interaction molecule 1 (STIM1) result in severe immune dysfunction and nonprogressive myopathy. Here, we identify gain-of-function mutations in the cytoplasmic domain of STIM1 (p.R304W) associated with thrombocytopenia, bleeding diathesis, miosis, and tubular myopathy in patients with Stormorken syndrome, and in ORAI1 (p.P245L), associated with a Stormorken-like syndrome of congenital miosis and tubular aggregate myopathy but without hematological abnormalities. Heterologous expression of STIM1 p.R304W results in constitutive activation of the CRAC channel in vitro, and spontaneous bleeding accompanied by reduced numbers of thrombocytes in zebrafish embryos, recapitulating key aspects of Stormorken syndrome. p.P245L in ORAI1 does not make a constitutively active CRAC channel, but suppresses the slow Ca(2+)-dependent inactivation of the CRAC channel, thus also functioning as a gain-of-function mutation. These data expand our understanding of the phenotypic spectrum of dysregulated CRAC channel signaling, advance our knowledge of the molecular function of the CRAC channel, and suggest new therapies aiming at attenuating store-operated Ca(2+) entry in the treatment of patients with Stormorken syndrome and related pathologic conditions.
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- 2014
30. Targeted resequencing and systematic in vivo functional testing identifies rare variants in MEIS1 as significant contributors to restless legs syndrome
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Maria Kousi, Annette Peters, Erik Tilch, Wolfgang H. Oertel, Ingo Fietze, Nicholas Katsanis, Klaus Berger, Juliane Winkelmann, Birgit Högl, Claudia Trenkwalder, Cornelius G. Bachmann, Perciliz L. Tan, Eva C. Schulte, Thomas Meitinger, Birgit Frauscher, Franziska Knauf, Bertram Müller-Myhsok, Christian Gieger, Alexander Zimprich, Peter Lichtner, and Magdolna Hornyak
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Nonsynonymous substitution ,Genotype ,Locus (genetics) ,Genome-wide association study ,Biology ,Article ,Mass Spectrometry ,03 medical and health sciences ,0302 clinical medicine ,Restless Legs Syndrome ,mental disorders ,Genetics ,Animals ,Humans ,Genetics(clinical) ,Allele ,Myeloid Ecotropic Viral Integration Site 1 Protein ,Genotyping ,Genetics (clinical) ,Loss function ,In Situ Hybridization ,Zebrafish ,030304 developmental biology ,Genetic association ,Homeodomain Proteins ,0303 health sciences ,Genetic Complementation Test ,Neoplasm Proteins ,030217 neurology & neurosurgery - Abstract
Restless legs syndrome (RLS) is a common neurologic condition characterized by nocturnal dysesthesias and an urge to move, affecting the legs. RLS is a complex trait, for which genome-wide association studies (GWASs) have identified common susceptibility alleles of modest (OR 1.2-1.7) risk at six genomic loci. Among these, variants in MEIS1 have emerged as the largest risk factors for RLS, suggesting that perturbations in this transcription factor might be causally related to RLS susceptibility. To establish this causality, direction of effect, and total genetic burden of MEIS1, we interrogated 188 case subjects and 182 control subjects for rare alleles not captured by previous GWASs, followed by genotyping of ∼3,000 case subjects and 3,000 control subjects, and concluded with systematic functionalization of all discovered variants using a previously established invivo model of neurogenesis. We observed a significant excess of rare MEIS1 variants in individuals with RLS. Subsequent assessment of all nonsynonymous variants by invivo complementation revealed an excess of loss-of-function alleles in individuals with RLS. Strikingly, these alleles compromised the function of the canonical MEIS1 splice isoform but were irrelevant to an isoform known to utilize an alternative 3' sequence. Our data link MEIS1 loss of function to the etiopathology of RLS, highlight how combined sequencing and systematic functional annotation of rare variation at GWAS loci can detect risk burden, and offer a plausible explanation for the specificity of phenotypic expressivity of loss-of-function alleles at a locus broadly necessary for neurogenesis and neurodevelopment.
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- 2014
31. Ataxia, Dementia, and Hypogonadotropism Caused by Disordered Ubiquitination
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Jennifer A. Chan, Stephanie B. Seminara, Jeremy D. Schmahmann, Jeff M. Milunsky, Lacey Plummer, Julia A. O'Rourke, David Margolin, Marios Hadjivassiliou, Elaine T. Lim, Nicholas Katsanis, Kasper Lage, Janet E. Hall, Stephanie V. Aldrin, Andrew A. Dwyer, E. Tessa Hedley-Whyte, Maria Kousi, Andrew Kirby, Mark J. Daly, Aubrey Milunsky, Yee-Ming Chan, and Ibrahim Adam
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Male ,medicine.medical_specialty ,Candidate gene ,Ataxia ,Ubiquitin-Protein Ligases ,Consanguinity ,Compound heterozygosity ,Article ,Hypogonadotropic hypogonadism ,Internal medicine ,medicine ,Animals ,Humans ,Exome ,Zebrafish ,Genetics ,biology ,Hypogonadism ,Ubiquitination ,General Medicine ,biology.organism_classification ,medicine.disease ,Ubiquitin ligase ,Pedigree ,Endocrinology ,biology.protein ,Dementia ,Female ,medicine.symptom - Abstract
The combination of ataxia and hypogonadism was first described more than a century ago, but its genetic basis has remained elusive.We performed whole-exome sequencing in a patient with ataxia and hypogonadotropic hypogonadism, followed by targeted sequencing of candidate genes in similarly affected patients. Neurologic and reproductive endocrine phenotypes were characterized in detail. The effects of sequence variants and the presence of an epistatic interaction were tested in a zebrafish model.Digenic homozygous mutations in RNF216 and OTUD4, which encode a ubiquitin E3 ligase and a deubiquitinase, respectively, were found in three affected siblings in a consanguineous family. Additional screening identified compound heterozygous truncating mutations in RNF216 in an unrelated patient and single heterozygous deleterious mutations in four other patients. Knockdown of rnf216 or otud4 in zebrafish embryos induced defects in the eye, optic tectum, and cerebellum; combinatorial suppression of both genes exacerbated these phenotypes, which were rescued by nonmutant, but not mutant, human RNF216 or OTUD4 messenger RNA. All patients had progressive ataxia and dementia. Neuronal loss was observed in cerebellar pathways and the hippocampus; surviving hippocampal neurons contained ubiquitin-immunoreactive intranuclear inclusions. Defects were detected at the hypothalamic and pituitary levels of the reproductive endocrine axis.The syndrome of hypogonadotropic hypogonadism, ataxia, and dementia can be caused by inactivating mutations in RNF216 or by the combination of mutations in RNF216 and OTUD4. These findings link disordered ubiquitination to neurodegeneration and reproductive dysfunction and highlight the power of whole-exome sequencing in combination with functional studies to unveil genetic interactions that cause disease. (Funded by the National Institutes of Health and others.).
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- 2013
32. Expression and lysosomal targeting of CLN7, a major facilitator superfamily transporter associated with variant late-infantile neuronal ceroid lipofuscinosis
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Raquel Ruivo, Anu Jalanko, Lydie Morel, Maria Kousi, Helena Hůlková, Gian Carlo Bellenchi, Anna-Elina Lehesjoki, Corinne Sagné, Aija Kyttälä, Milan Elleder, Cécile Debacker, Bruno Gasnier, S. El Mestikawy, Azita Sharifi, and Michèle Darmon
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Batten disease ,Transfection ,Rats, Sprague-Dawley ,03 medical and health sciences ,0302 clinical medicine ,Neuronal Ceroid-Lipofuscinoses ,Lysosome ,Genetics ,medicine ,Animals ,Humans ,RNA, Messenger ,Molecular Biology ,Gene ,Genetics (clinical) ,Cells, Cultured ,030304 developmental biology ,0303 health sciences ,biology ,Membrane transport protein ,HEK 293 cells ,Homozygote ,Brain ,Membrane Transport Proteins ,General Medicine ,Articles ,medicine.disease ,Transmembrane protein ,Major facilitator superfamily ,Cell biology ,Rats ,Transcription Factor AP-1 ,medicine.anatomical_structure ,HEK293 Cells ,Membrane protein ,Animals, Newborn ,Mutation ,biology.protein ,Lysosomes ,030217 neurology & neurosurgery ,HeLa Cells - Abstract
Neuronal ceroid lipofuscinoses (NCLs) constitute a group of progressive neurodegenerative disorders resulting from mutations in at least eight different genes. Mutations in the most recently identified NCL gene, MFSD8/CLN7, underlie a variant of late-infantile NCL (vLINCL). The MFSD8/CLN7 gene encodes a polytopic protein with unknown function, which shares homology with ion-coupled membrane transporters. In this study, we confirmed the lysosomal localization of the native CLN7 protein. This localization of CLN7 is not impaired by the presence of pathogenic missense mutations or after genetic ablation of the N-glycans. Expression of chimeric and full-length constructs showed that lysosomal targeting of CLN7 is mainly determined by an N-terminal dileucine motif, which specifically binds to the heterotetrameric adaptor AP-1 in vitro. We also show that CLN7 mRNA is more abundant in neurons than astrocytes and microglia, and that it is expressed throughout rat brain, with increased levels in the granular layer of cerebellum and hippocampal pyramidal cells. Interestingly, this cellular and regional distribution is in good agreement with the autofluorescent lysosomal storage and cell loss patterns found in brains from CLN7-defective patients. Overall, these data highlight lysosomes as the primary site of action for CLN7, and suggest that the pathophysiology underpinning CLN7-associated vLINCL is a cell-autonomous process.
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- 2010
33. Mutations in CLN7/MFSD8 are a common cause of variant late-infantile neuronal ceroid lipofuscinosis.
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Maria Kousi, Eija Siintola, Lenka Dvorakova, Hana Vlaskova, Julie Turnbull, Meral Topcu, Deniz Yuksel, Sarenur Gokben, Berge A. Minassian, Milan Elleder, Sara E. Mole, and Anna-Elina Lehesjoki
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GENETIC mutation , *NEURONAL ceroid-lipofuscinosis , *JUVENILE diseases , *PHENOTYPES , *AMINO acid sequence , *GENETICS - Abstract
The neuronal ceroid lipofuscinoses (NCLs), the most common neurodegenerative disorders of childhood, are characterized by the accumulation of autofluorescent storage material mainly in neurons. Although clinically rather uniform, variant late-infantile onset NCL (vLINCL) is genetically heterogeneous with four major underlying genes identified so far. We evaluated the genetic background underlying vLINCL in 119 patients, and specifically analysed the recently reported CLN7/MFSD8 gene for mutations in 80 patients. Clinical data were collected from the CLN7/MFSD8 mutation positive patients. Eight novel CLN7/MFSD8 mutations and seven novel mutations in the CLN1/PPT1, CLN2/TPP1, CLN5, CLN6 and CLN8 genes were identified in patients of various ethnic origins. A significant group of Roma patients originating from the former Czechoslovakia was shown to bear the c.881C>A (p.Thr294Lys) mutation in CLN7/MFSD8, possibly due to a founder effect. With one exception, the CLN7/MFSD8 mutation positive patients present a phenotype indistinguishable from the other vLINCL forms. In one patient with an in-frame amino acid substitution mutation in CLN7/MFSD8, the disease onset was later and the disease course less aggressive than in variant late-infantile NCL. Our findings raise the total number of CLN7/MFSD8 mutations to 14 with the majority of families having private mutations. Our study confirms that CLN7/MFSD8 defects are not restricted to the Turkish population, as initially anticipated, but are a relatively common cause of NCL in different populations. CLN7/MFSD8 should be considered a diagnostic alternative not only in variant late-infantile but also later onset NCL forms with a more protracted disease course. A significant number of NCL patients in Turkey exist, in which the underlying genetic defect remains to be determined. [ABSTRACT FROM AUTHOR]
- Published
- 2009
- Full Text
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