Search

Your search keyword '"Arts, Heleen H"' showing total 5 results
Start Over Author "Arts, Heleen H" Topic genetics
5 results on '"Arts, Heleen H"'

1. A mutation in IFT43 causes non-syndromic recessive retinal degeneration

Author

Biswas, Pooja, Duncan, Jacque L, Ali, Muhammad, Matsui, Hiroko, Naeem, Muhammad Asif, Raghavendra, Pongali B, Frazer, Kelly A, Arts, Heleen H, Riazuddin, Sheikh, Akram, Javed, Hejtmancik, J Fielding, Riazuddin, S Amer, and Ayyagari, Radha

Subjects
Biological Sciences, Genetics, Rare Diseases, Neurodegenerative, Pediatric, Neurosciences, Eye Disease and Disorders of Vision, Biotechnology, Clinical Research, 2.1 Biological and endogenous factors, Eye, Base Sequence, Carrier Proteins, Consanguinity, Exome, Female, Genes, Recessive, Homozygote, Humans, Male, Mutation, Pedigree, Phenotype, Retina, Retinal Degeneration, Exome Sequencing, Medical and Health Sciences, Genetics & Heredity
Abstract

The aim of this work is to identify the molecular cause of autosomal recessive early onset retinal degeneration in a consanguineous pedigree. Seventeen members of a four-generation Pakistani family were recruited and underwent a detailed ophthalmic examination. Exomes of four affected and two unaffected individuals were sequenced. Variants were filtered using exomeSuite to identify rare potentially pathogenic variants in genes expressed in the retina and/or brain and consistent with the pattern of inheritance. Effect of the variant observed in the gene Intraflagellar Transport Protein 43 (IFT43) was studied by heterologous expression in mIMCD3 and MDCK cells. Expression and sub-cellular localization of IFT43 in the retina and transiently transfected cells was examined by RT-PCR, western blot analysis, and immunohistochemistry. Affected members were diagnosed with early onset non-syndromic progressive retinal degeneration and the presence of bone spicules distributed throughout the retina at younger ages while the older affected members showed severe central choroidal atrophy. Whole-exome sequencing analysis identified a novel homozygous c.100 G > A change in IFT43 segregating with retinal degeneration and not present in ethnicity-matched controls. Immunostaining showed IFT43 localized in the photoreceptors, and to the tip of the cilia in transfected mIMCD3 and MDCK cells. The cilia in mIMCD3 and MDCK cells expressing mutant IFT43 were found to be significantly shorter (P

Published
2017

2. Clinical and genetic analyses of a Dutch cohort of 40 patients with a nephronophthisis-related ciliopathy.

Author

Stokman, Marijn F., van der Zwaag, Bert, van de Kar, Nicole C. A. J., van Haelst, Mieke M., van Eerde, Albertien M., van der Heijden, Joost W., Kroes, Hester Y., Ippel, Elly, Schulp, Annelien J. A., van Gassen, Koen L., van Rooij, Iris A. L. M., Giles, Rachel H., Beales, Philip L., Roepman, Ronald, Arts, Heleen H., Bongers, Ernie M. H. F., Renkema, Kirsten Y., Knoers, Nine V. A. M., van Reeuwijk, Jeroen, and Lilien, Marc R.

Subjects
ACADEMIC medical centers, AGE distribution, BIOPSY, CHRONIC kidney failure, CYSTS (Pathology), FATIGUE (Physiology), GENETIC counseling, HYPERTENSION, INTERNET, LONGITUDINAL method, CYSTIC kidney disease, ULTRASONIC imaging, GENETIC testing, POLYURIA, EARLY diagnosis, POLYDIPSIA, GENOTYPES, DISEASE complications, CILIOPATHY, SYMPTOMS, GENETICS, DIAGNOSIS
Abstract

Background: Nephronophthisis is an autosomal recessive ciliopathy and important cause of end-stage renal disease (ESRD) in children and young adults. Diagnostic delay is frequent. This study investigates clinical characteristics, initial symptoms, and genetic defects in a cohort with nephronophthisis-related ciliopathy, to improve early detection and genetic counseling.Methods: Forty patients from 36 families with nephronophthisis-related ciliopathy were recruited at university medical centers and online. Comprehensive clinical and genotypic data were recorded. Patients without molecular diagnosis were offered genetic analysis.Results: Of 40 patients, 45% had isolated nephronophthisis, 48% syndromic diagnosis, and 7% nephronophthisis with extrarenal features not constituting a recognizable syndrome. Patients developed ESRD at median 13 years (range 5-47). Median age of symptom onset was 9 years in both isolated and syndromic forms (range 5-26 vs. 5-33). Common presenting symptoms were fatigue (42%), polydipsia/polyuria (33%), and hypertension (21%). Renal ultrasound showed small-to-normal-sized kidneys, increased echogenicity (65%), cysts (43%), and abnormal corticomedullary differentiation (32%). Renal biopsies in eight patients showed nonspecific signs of chronic kidney disease (CKD). Twenty-three patients (58%) had genetic diagnosis upon inclusion. Thirteen of those without a genetic diagnosis gave consent for genetic testing, and a cause was identified in five (38%).Conclusions: Nephronophthisis is genetically and phenotypically heterogeneous and should be considered in children and young adults presenting with persistent fatigue and polyuria, and in all patients with unexplained CKD. As symptom onset can occur into adulthood, presymptomatic monitoring of kidney function in syndromic ciliopathy patients should continue until at least age 30. [ABSTRACT FROM AUTHOR]

Published
2018
Full Text
View/download PDF

3. Mutations in the Gene Encoding IFT Dynein Complex Component WDR34 Cause Jeune Asphyxiating Thoracic Dystrophy

Author

Schmidts, Miriam, Vodopiutz, Julia, Christou-Savina, Sonia, Cortés, Claudio R., McInerney-Leo, Aideen M., Emes, Richard D., Arts, Heleen H., Tüysüz, Beyhan, D’Silva, Jason, Leo, Paul J., Giles, Tom C., Oud, Machteld M., Harris, Jessica A., Koopmans, Marije, Marshall, Mhairi, Elçioglu, Nursel, Kuechler, Alma, Bockenhauer, Detlef, Moore, Anthony T., Wilson, Louise C., Janecke, Andreas R., Hurles, Matthew E., Emmet, Warren, Gardiner, Brooke, Streubel, Berthold, Dopita, Belinda, Zankl, Andreas, Kayserili, Hülya, Scambler, Peter J., Brown, Matthew A., Beales, Philip L., Wicking, Carol, Duncan, Emma L., and Mitchison, Hannah M.

Subjects
Cytoplasmic Dyneins, Proteomics, Axoneme, Ellis-Van Creveld Syndrome, Protein Conformation, Chlamydomonas, Infant, Newborn, Intracellular Signaling Peptides and Proteins, Medizin, Infant, Exons, White People, Asian People, Report, Mutation, Genetics, Animals, Humans, Exome, Genetics(clinical), Cilia, sense organs, Carrier Proteins, Child, Cytoskeleton
Abstract

Bidirectional (anterograde and retrograde) motor-based intraflagellar transport (IFT) governs cargo transport and delivery processes that are essential for primary cilia growth and maintenance and for hedgehog signaling functions. The IFT dynein-2 motor complex that regulates ciliary retrograde protein transport contains a heavy chain dynein ATPase/motor subunit, DYNC2H1, along with other less well functionally defined subunits. Deficiency of IFT proteins, including DYNC2H1, underlies a spectrum of skeletal ciliopathies. Here, by using exome sequencing and a targeted next-generation sequencing panel, we identified a total of 11 mutations in WDR34 in 9 families with the clinical diagnosis of Jeune syndrome (asphyxiating thoracic dystrophy). WDR34 encodes a WD40 repeat-containing protein orthologous to Chlamydomonas FAP133, a dynein intermediate chain associated with the retrograde intraflagellar transport motor. Three-dimensional protein modeling suggests that the identified mutations all affect residues critical for WDR34 protein-protein interactions. We find that WDR34 concentrates around the centrioles and basal bodies in mammalian cells, also showing axonemal staining. WDR34 coimmunoprecipitates with the dynein-1 light chain DYNLL1 in vitro, and mining of proteomics data suggests that WDR34 could represent a previously unrecognized link between the cytoplasmic dynein-1 and IFT dynein-2 motors. Together, these data show that WDR34 is critical for ciliary functions essential to normal development and survival, most probably as a previously unrecognized component of the mammalian dynein-IFT machinery. © 2013 by The American Society of Human Genetics. All rights reserved.

Full Text
View/download PDF

4. Exome sequencing identifies WDR35 variants involved in Sensenbrenner syndrome

Author

Dorus A. Mans, Liesbeth Spruijt, Heleen H. Arts, Bart van Lier, Ronald Roepman, Alexander Hoischen, Peer Arts, Han G. Brunner, Christian Gilissen, Sarina G. Kant, Nine V A M Knoers, Joris A. Veltman, Marloes Steehouwer, Jeroen van Reeuwijk, Gilissen, Christian, Arts, Heleen H, Hoischen, Alexander, Spruijt, Liesbeth, Mans, Dorus A, Arts, Peer, Van Lier, Bart, Steehouwer, Marloes, Van Reeuwijk, Jeroen, Kant, Sarina G, Roepman, Ronald, Knoers, Nine V A M, Veltman, Joris A, and Brunner, Han G

Subjects
Genetics and epigenetic pathways of disease [NCMLS 6], DNA Mutational Analysis, Compound heterozygosity, Exon, 0302 clinical medicine, Ectodermal Dysplasia, Abnormalities, Multiple/genetics, Exons/genetics, Genetics(clinical), Child, RNA Splice Sites/genetics, Exome, Genetics (clinical), Exome sequencing, Renal disorder [IGMD 9], Genetics, 0303 health sciences, Exons, Syndrome, Ectodermal Dysplasia/genetics, 3. Good health, Sensenbrenner syndrome, DNA/methods, Sequence Analysis, DNA/methods, Multiple/genetics, Abnormalities, Sequence Analysis, asphyxiating thoracic dystrophy cranioectodermal dysplasia retinal degeneration mutations mouse cilia protein obesity genome tulp3, Mutation/genetics, WDR35, Molecular Sequence Data, Biology, Genomic disorders and inherited multi-system disorders [IGMD 3], 03 medical and health sciences, Intraflagellar transport, Report, medicine, Humans, Abnormalities, Multiple, Allele, Membrane Proteins/genetics, 030304 developmental biology, Base Sequence, Membrane Proteins, Sequence Analysis, DNA, medicine.disease, Molecular biology, Mutation, Apoptosis Regulatory Proteins/genetics, RNA Splice Sites, Apoptosis Regulatory Proteins, Cranioectodermal Dysplasia, exome sequencing, 030217 neurology & neurosurgery
Abstract

Contains fulltext : 88664.pdf (Publisher’s version ) (Closed access) Sensenbrenner syndrome/cranioectodermal dysplasia (CED) is an autosomal-recessive disease that is characterized by craniosynostosis and ectodermal and skeletal abnormalities. We sequenced the exomes of two unrelated CED patients and identified compound heterozygous mutations in WDR35 as the cause of the disease in each of the two patients independently, showing that it is possible to find the causative gene by sequencing the exome of a single sporadic patient. With RT-PCR, we demonstrate that a splice-site mutation in exon 2 of WDR35 alters splicing of RNA on the affected allele, introducing a premature stop codon. WDR35 is homologous to TULP4 (from the Tubby superfamily) and has previously been characterized as an intraflagellar transport component, confirming that Sensenbrenner syndrome is a ciliary disorder.

Published
2010
Full Text
View/download PDF

5. Exome sequencing identifies DYNC2H1 mutations as a common cause of asphyxiating thoracic dystrophy (Jeune syndrome) without major polydactyly, renal or retinal involvement

Author

Schmidts, M., Arts, H.H., Bongers, E.M., Yap, Z., Oud, M.M., Antony, D., Duijkers, L., Emes, R.D., Stalker, J., Yntema, J.B., Plagnol, V., Hoischen, A., Gilissen, C., Forsythe, E., Lausch, E., Veltman, J.A., Roeleveld, N., Superti-Furga, A., Kutkowska-Kazmierczak, A., Kamsteeg, E.J., Elçioglu, N., van Maarle, M.C., Graul-Neumann, L.M., Devriendt, K., Smithson, S.F., Wellesley, D., Verbeek, N.E., Hennekam, R.C., Kayserili, H., Scambler, P.J., Beales, P.L., UK10K, Knoers, N.V., Roepman, R., Mitchison, H.M., Schmidts, Miriam, Arts, Heleen H., Bongers, Ernie M. H. F., Yap, Zhimin, Oud, Machteld M., Antony, Dinu, Duijkers, Lonneke, Emes, Richard D., Stalker, Jim, Yntema, Jan-Bart L., Plagnol, Vincent, Hoischen, Alexander, Gilissen, Christian, Forsythe, Elisabeth, Lausch, Ekkehart, Veltman, Joris A., Roeleveld, Nel, Superti-Furga, Andrea, Kutkowska-Kazmierczak, Anna, Kamsteeg, Erik-Jan, Elcioglu, Nursel, van Maarle, Merel C., Graul-Neumann, Luitgard M., Devriendt, Koenraad, Smithson, Sarah F., Wellesley, Diana, Verbeek, Nienke E., Hennekam, Raoul C. M., Kayserili, Hulya, Scambler, Peter J., Beales, Philip L., Knoers, Nine V. A. M., Roepman, Ronald, Mitchison, Hannah M., Human Genetics, ANS - Amsterdam Neuroscience, APH - Amsterdam Public Health, Paediatrics, and UK10K

Subjects
Exome/genetics, Cytoplasmic Dyneins, Models, Molecular, Genetics and epigenetic pathways of disease [NCMLS 6], Protein Conformation, Bioinformatics, medicine.disease_cause, 0302 clinical medicine, Models, Genetic Screening/Counselling, Missense mutation, Developmental, Exome, CRYSTAL-STRUCTURE, Diagnostics, Genetics (clinical), Exome sequencing, Renal disorder [IGMD 9], Genetics, Microscopy, 0303 health sciences, Mutation, Polydactyly, Developmental Defects, DEFECTS, Polymorphism, Single Nucleotide/genetics, 3. Good health, Gene Components, Ellis-Van Creveld Syndrome/genetics, PELVIC-PHALANGEAL DYSTROPHY, Single Nucleotide/genetics, Sequence Analysis, Mutation/genetics, Ellis-Van Creveld Syndrome, Molecular Sequence Data, IFT, Biology, DYNEIN MOTOR DOMAIN, Polymorphism, Single Nucleotide, Fluorescence, Frameshift mutation, Genomic disorders and inherited multi-system disorders [IGMD 3], Molecular Genetics, 03 medical and health sciences, Intraflagellar transport, CYTOPLASMIC DYNEIN, medicine, RETROGRADE INTRAFLAGELLAR TRANSPORT, Humans, Polymorphism, 030304 developmental biology, Clinical Genetics, Base Sequence, Genetic heterogeneity, Molecular, DNA, Sequence Analysis, DNA, Human Reproducion Genomic disorders and inherited multi-system disorders [NCEBP 12], medicine.disease, LIGHT INTERMEDIATE CHAIN, Microscopy, Fluorescence, Cytoplasmic Dyneins/chemistry, Genetics and epigenetic pathways of disease Renal disorder [NCMLS 6], PRIMARY CILIARY DYSKINESIA, Genetics and epigenetic pathways of disease Genomic disorders and inherited multi-system disorders [NCMLS 6], CAENORHABDITIS-ELEGANS, 030217 neurology & neurosurgery
Abstract

Contains fulltext : 116495.pdf (Publisher’s version ) (Open Access) BACKGROUND: Jeune asphyxiating thoracic dystrophy (JATD) is a rare, often lethal, recessively inherited chondrodysplasia characterised by shortened ribs and long bones, sometimes accompanied by polydactyly, and renal, liver and retinal disease. Mutations in intraflagellar transport (IFT) genes cause JATD, including the IFT dynein-2 motor subunit gene DYNC2H1. Genetic heterogeneity and the large DYNC2H1 gene size have hindered JATD genetic diagnosis. AIMS AND METHODS: To determine the contribution to JATD we screened DYNC2H1 in 71 JATD patients JATD patients combining SNP mapping, Sanger sequencing and exome sequencing. RESULTS AND CONCLUSIONS: We detected 34 DYNC2H1 mutations in 29/71 (41%) patients from 19/57 families (33%), showing it as a major cause of JATD especially in Northern European patients. This included 13 early protein termination mutations (nonsense/frameshift, deletion, splice site) but no patients carried these in combination, suggesting the human phenotype is at least partly hypomorphic. In addition, 21 missense mutations were distributed across DYNC2H1 and these showed some clustering to functional domains, especially the ATP motor domain. DYNC2H1 patients largely lacked significant extra-skeletal involvement, demonstrating an important genotype-phenotype correlation in JATD. Significant variability exists in the course and severity of the thoracic phenotype, both between affected siblings with identical DYNC2H1 alleles and among individuals with different alleles, which suggests the DYNC2H1 phenotype might be subject to modifier alleles, non-genetic or epigenetic factors. Assessment of fibroblasts from patients showed accumulation of anterograde IFT proteins in the ciliary tips, confirming defects similar to patients with other retrograde IFT machinery mutations, which may be of undervalued potential for diagnostic purposes. 15 p.

Published
2013

Catalog

Books, media, physical & digital resources
See catalog results