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1. A phenotypic spectrum of autism is attributable to the combined effects of rare variants, polygenic risk and sex

Author

Antaki, Danny, Guevara, James, Maihofer, Adam X, Klein, Marieke, Gujral, Madhusudan, Grove, Jakob, Carey, Caitlin E, Hong, Oanh, Arranz, Maria J, Hervas, Amaia, Corsello, Christina, Vaux, Keith K, Muotri, Alysson R, Iakoucheva, Lilia M, Courchesne, Eric, Pierce, Karen, Gleeson, Joseph G, Robinson, Elise B, Nievergelt, Caroline M, and Sebat, Jonathan

Subjects
Biological Sciences, Genetics, Brain Disorders, Intellectual and Developmental Disabilities (IDD), Autism, Mental Health, Neurosciences, Prevention, Pediatric, 2.1 Biological and endogenous factors, 2.4 Surveillance and distribution, Mental health, Autism Spectrum Disorder, Autistic Disorder, Child, Family, Female, Genetic Predisposition to Disease, Humans, Male, Multifactorial Inheritance, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

The genetic etiology of autism spectrum disorder (ASD) is multifactorial, but how combinations of genetic factors determine risk is unclear. In a large family sample, we show that genetic loads of rare and polygenic risk are inversely correlated in cases and greater in females than in males, consistent with a liability threshold that differs by sex. De novo mutations (DNMs), rare inherited variants and polygenic scores were associated with various dimensions of symptom severity in children and parents. Parental age effects on risk for ASD in offspring were attributable to a combination of genetic mechanisms, including DNMs that accumulate in the paternal germline and inherited risk that influences behavior in parents. Genes implicated by rare variants were enriched in excitatory and inhibitory neurons compared with genes implicated by common variants. Our results suggest that a phenotypic spectrum of ASD is attributable to a spectrum of genetic factors that impact different neurodevelopmental processes.

Published
2022

2. Biallelic Mutations in ADPRHL2, Encoding ADP-Ribosylhydrolase 3, Lead to a Degenerative Pediatric Stress-Induced Epileptic Ataxia Syndrome

Author

Ghosh, Shereen G, Becker, Kerstin, Huang, He, Dixon-Salazar, Tracy, Chai, Guoliang, Salpietro, Vincenzo, Al-Gazali, Lihadh, Waisfisz, Quinten, Wang, Haicui, Vaux, Keith K, Stanley, Valentina, Manole, Andreea, Akpulat, Ugur, Weiss, Marjan M, Efthymiou, Stephanie, Hanna, Michael G, Minetti, Carlo, Striano, Pasquale, Pisciotta, Livia, De Grandis, Elisa, Altmüller, Janine, Weixler, Lisa, Nürnberg, Peter, Thiele, Holger, Yis, Uluc, Okur, Tuncay Derya, Polat, Ayse Ipek, Amiri, Nafise, Doosti, Mohammad, Karimani, Ehsan Ghayoor, Toosi, Mehran B, Haddad, Gabriel, Karakaya, Mert, Wirth, Brunhilde, van Hagen, Johanna M, Wolf, Nicole I, Maroofian, Reza, Houlden, Henry, Cirak, Sebahattin, and Gleeson, Joseph G

Subjects
Biochemistry and Cell Biology, Genetics, Biological Sciences, Epilepsy, Pediatric, Brain Disorders, Neurosciences, Rare Diseases, Neurodegenerative, Aetiology, 2.1 Biological and endogenous factors, Neurological, ADP-ribosylation, ADPRHL2, ARH3, SUDEP, ataxia, epilepsy, neurodegeneration, neuropathy, oxidative stress, poly-ADP ribose, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

ADP-ribosylation, the addition of poly-ADP ribose (PAR) onto proteins, is a response signal to cellular challenges, such as excitotoxicity or oxidative stress. This process is catalyzed by a group of enzymes referred to as poly(ADP-ribose) polymerases (PARPs). Because the accumulation of proteins with this modification results in cell death, its negative regulation restores cellular homeostasis: a process mediated by poly-ADP ribose glycohydrolases (PARGs) and ADP-ribosylhydrolase proteins (ARHs). Using linkage analysis and exome or genome sequencing, we identified recessive inactivating mutations in ADPRHL2 in six families. Affected individuals exhibited a pediatric-onset neurodegenerative disorder with progressive brain atrophy, developmental regression, and seizures in association with periods of stress, such as infections. Loss of the Drosophila paralog Parg showed lethality in response to oxidative challenge that was rescued by human ADPRHL2, suggesting functional conservation. Pharmacological inhibition of PARP also rescued the phenotype, suggesting the possibility of postnatal treatment for this genetic condition.

Published
2018

3. Paternally inherited cis-regulatory structural variants are associated with autism

Author

Brandler, William M, Antaki, Danny, Gujral, Madhusudan, Kleiber, Morgan L, Whitney, Joe, Maile, Michelle S, Hong, Oanh, Chapman, Timothy R, Tan, Shirley, Tandon, Prateek, Pang, Timothy, Tang, Shih C, Vaux, Keith K, Yang, Yan, Harrington, Eoghan, Juul, Sissel, Turner, Daniel J, Thiruvahindrapuram, Bhooma, Kaur, Gaganjot, Wang, Zhuozhi, Kingsmore, Stephen F, Gleeson, Joseph G, Bisson, Denis, Kakaradov, Boyko, Telenti, Amalio, Venter, J Craig, Corominas, Roser, Toma, Claudio, Cormand, Bru, Rueda, Isabel, Guijarro, Silvina, Messer, Karen S, Nievergelt, Caroline M, Arranz, Maria J, Courchesne, Eric, Pierce, Karen, Muotri, Alysson R, Iakoucheva, Lilia M, Hervas, Amaia, Scherer, Stephen W, Corsello, Christina, and Sebat, Jonathan

Subjects
Biological Sciences, Genetics, Pediatric, Mental Health, Clinical Research, Autism, Intellectual and Developmental Disabilities (IDD), Brain Disorders, 2.1 Biological and endogenous factors, Mental health, Autism Spectrum Disorder, Exons, Gene Expression Regulation, Genetic Predisposition to Disease, Genetic Variation, Genome, Human, Humans, Mutation, Paternal Inheritance, Pedigree, Promoter Regions, Genetic, RNA, Untranslated, Selection, Genetic, Sequence Deletion, Transcription Factors, General Science & Technology
Abstract

The genetic basis of autism spectrum disorder (ASD) is known to consist of contributions from de novo mutations in variant-intolerant genes. We hypothesize that rare inherited structural variants in cis-regulatory elements (CRE-SVs) of these genes also contribute to ASD. We investigated this by assessing the evidence for natural selection and transmission distortion of CRE-SVs in whole genomes of 9274 subjects from 2600 families affected by ASD. In a discovery cohort of 829 families, structural variants were depleted within promoters and untranslated regions, and paternally inherited CRE-SVs were preferentially transmitted to affected offspring and not to their unaffected siblings. The association of paternal CRE-SVs was replicated in an independent sample of 1771 families. Our results suggest that rare inherited noncoding variants predispose children to ASD, with differing contributions from each parent.

Published
2018

4. Frequency and Complexity of De Novo Structural Mutation in Autism

Author

Brandler, William M, Antaki, Danny, Gujral, Madhusudan, Noor, Amina, Rosanio, Gabriel, Chapman, Timothy R, Barrera, Daniel J, Lin, Guan Ning, Malhotra, Dheeraj, Watts, Amanda C, Wong, Lawrence C, Estabillo, Jasper A, Gadomski, Therese E, Hong, Oanh, Fajardo, Karin V Fuentes, Bhandari, Abhishek, Owen, Renius, Baughn, Michael, Yuan, Jeffrey, Solomon, Terry, Moyzis, Alexandra G, Maile, Michelle S, Sanders, Stephan J, Reiner, Gail E, Vaux, Keith K, Strom, Charles M, Zhang, Kang, Muotri, Alysson R, Akshoomoff, Natacha, Leal, Suzanne M, Pierce, Karen, Courchesne, Eric, Iakoucheva, Lilia M, Corsello, Christina, and Sebat, Jonathan

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Pediatric, Autism, Human Genome, Brain Disorders, Mental Health, Intellectual and Developmental Disabilities (IDD), Biotechnology, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Alleles, Amino Acid Sequence, Autism Spectrum Disorder, Base Sequence, Case-Control Studies, Child, DNA Copy Number Variations, Female, Gene Deletion, Gene Duplication, Gene Frequency, Gene Rearrangement, Genetic Loci, Genome, Human, Genotyping Techniques, Humans, INDEL Mutation, Male, Microarray Analysis, Molecular Sequence Data, Pedigree, Reproducibility of Results, Sensitivity and Specificity, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Genetic studies of autism spectrum disorder (ASD) have established that de novo duplications and deletions contribute to risk. However, ascertainment of structural variants (SVs) has been restricted by the coarse resolution of current approaches. By applying a custom pipeline for SV discovery, genotyping, and de novo assembly to genome sequencing of 235 subjects (71 affected individuals, 26 healthy siblings, and their parents), we compiled an atlas of 29,719 SV loci (5,213/genome), comprising 11 different classes. We found a high diversity of de novo mutations, the majority of which were undetectable by previous methods. In addition, we observed complex mutation clusters where combinations of de novo SVs, nucleotide substitutions, and indels occurred as a single event. We estimate a high rate of structural mutation in humans (20%) and propose that genetic risk for ASD is attributable to an elevated frequency of gene-disrupting de novo SVs, but not an elevated rate of genome rearrangement.

Published
2016

5. Extending the mutation spectrum for Galloway–Mowat syndrome to include homozygous missense mutations in the WDR73 gene

Author

Rosti, Rasim O, Dikoglu, Esra, Zaki, Maha S, Abdel-Salam, Ghada, Makhseed, Nawal, Sese, Jordan C, Musaev, Damir, Rosti, Basak, Harbert, Mary J, Jones, Marilyn C, Vaux, Keith K, and Gleeson, Joseph G

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Biomedical and Clinical Sciences, Genetics, Rare Diseases, Congenital Structural Anomalies, Neurodegenerative, Intellectual and Developmental Disabilities (IDD), Clinical Research, Pediatric, Neurosciences, Brain Disorders, Aetiology, 2.1 Biological and endogenous factors, Congenital, Cohort Studies, Exome, Facies, Female, Genetic Association Studies, Hernia, Hiatal, High-Throughput Nucleotide Sequencing, Homozygote, Humans, Male, Microcephaly, Models, Molecular, Mutation, Missense, Nephrosis, Pedigree, Phenotype, Protein Conformation, Proteins, Galloway-Mowat syndrome, cerebellar atrophy, coarse face, WDR73, nephrotic syndrome, Clinical Sciences, Clinical sciences
Abstract

Galloway-Mowat syndrome is a rare autosomal-recessive disorder classically described as the combination of microcephaly and nephrotic syndrome. Recently, homozygous truncating mutations in WDR73 (WD repeat domain 73) were described in two of 31 unrelated families with Galloway-Mowat syndrome which was followed by a report of two sibs in an Egyptian consanguineous family. In this report, seven affecteds from four families showing biallelic missense mutations in WDR73 were identified by exome sequencing and confirmed to follow a recessive model of inheritance. Three-dimensional modeling predicted conformational alterations as a result of the mutation, supporting pathogenicity. An additional 13 families with microcephaly and renal phenotype were negative for WDR73 mutations. Missense mutations in the WDR73 gene are reported for the first time in Galloway-Mowat syndrome. A detailed phenotypic comparison of all reported WDR73-linked Galloway-Mowat syndrome patients with WDR73 negative patients showed that WDR73 mutations are limited to those with classical Galloway-Mowat syndrome features, in addition to cerebellar atrophy, thin corpus callosum, brain stem hypoplasia, occasional coarse face, late-onset and mostly slow progressive nephrotic syndrome, and frequent epilepsy.

Published
2016

6. Biallelic mutations in SNX14 cause a syndromic form of cerebellar atrophy and lysosome-autophagosome dysfunction

Author

Akizu, Naiara, Cantagrel, Vincent, Zaki, Maha S, Al-Gazali, Lihadh, Wang, Xin, Rosti, Rasim Ozgur, Dikoglu, Esra, Gelot, Antoinette Bernabe, Rosti, Basak, Vaux, Keith K, Scott, Eric M, Silhavy, Jennifer L, Schroth, Jana, Copeland, Brett, Schaffer, Ashleigh E, Gordts, Philip LSM, Esko, Jeffrey D, Buschman, Matthew D, Field, Seth J, Napolitano, Gennaro, Abdel-Salam, Ghada M, Ozgul, R Koksal, Sagıroglu, Mahmut Samil, Azam, Matloob, Ismail, Samira, Aglan, Mona, Selim, Laila, Mahmoud, Iman G, Abdel-Hadi, Sawsan, Badawy, Amera El, Sadek, Abdelrahim A, Mojahedi, Faezeh, Kayserili, Hulya, Masri, Amira, Bastaki, Laila, Temtamy, Samia, Müller, Ulrich, Desguerre, Isabelle, Casanova, Jean-Laurent, Dursun, Ali, Gunel, Murat, Gabriel, Stacey B, de Lonlay, Pascale, and Gleeson, Joseph G

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Brain Disorders, Clinical Research, Animals, Atrophy, Autophagy, Cerebellar Diseases, Cerebellum, Child, Preschool, Female, Gene Frequency, Humans, Infant, Lod Score, Lysosomal Storage Diseases, Lysosomes, Male, Mutation, Phagosomes, Sorting Nexins, Spinocerebellar Ataxias, Syndrome, Zebrafish, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology, Genetics
Abstract

Pediatric-onset ataxias often present clinically as developmental delay and intellectual disability, with prominent cerebellar atrophy as a key neuroradiographic finding. Here we describe a new clinically distinguishable recessive syndrome in 12 families with cerebellar atrophy together with ataxia, coarsened facial features and intellectual disability, due to truncating mutations in the sorting nexin gene SNX14, encoding a ubiquitously expressed modular PX domain-containing sorting factor. We found SNX14 localized to lysosomes and associated with phosphatidylinositol (3,5)-bisphosphate, a key component of late endosomes/lysosomes. Patient-derived cells showed engorged lysosomes and a slower autophagosome clearance rate upon autophagy induction by starvation. Zebrafish morphants for snx14 showed dramatic loss of cerebellar parenchyma, accumulation of autophagosomes and activation of apoptosis. Our results characterize a unique ataxia syndrome due to biallelic SNX14 mutations leading to lysosome-autophagosome dysfunction.

Published
2015

7. Publisher Correction: A phenotypic spectrum of autism is attributable to the combined effects of rare variants, polygenic risk and sex

Author

Antaki, Danny, Guevara, James, Maihofer, Adam X., Klein, Marieke, Gujral, Madhusudan, Grove, Jakob, Carey, Caitlin E., Hong, Oanh, Arranz, Maria J., Hervas, Amaia, Corsello, Christina, Vaux, Keith K., Muotri, Alysson R., Iakoucheva, Lilia M., Courchesne, Eric, Pierce, Karen, Gleeson, Joseph G., Robinson, Elise B., Nievergelt, Caroline M., and Sebat, Jonathan

Published
2022
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8. Exome Sequencing Links Corticospinal Motor Neuron Disease to Common Neurodegenerative Disorders

Author

Novarino, Gaia, Fenstermaker, Ali G., Zaki, Maha S., Hofree, Matan, Silhavy, Jennifer L., Heiberg, Andrew D., Abdellateef, Mostafa, Rosti, Basak, Scott, Eric, Mansour, Lobna, Masri, Amira, Kayserili, Hulya, Al-Aama, Jumana Y., Abdel-Salam, Ghada M. H., Karminejad, Ariana, Kara, Majdi, Kara, Bulent, Bozorgmehri, Bita, Ben-Omran, Tawfeg, Mojahedi, Faezeh, Mahmoud, Iman Gamal El Din, Bouslam, Naima, Bouhouche, Ahmed, Benomar, Ali, Hanein, Sylvain, Raymond, Laure, Forlani, Sylvie, Mascaro, Massimo, Selim, Laila, Shehata, Nabil, Al-Allawi, Nasir, Bindu, P.S., Azam, Matloob, Gunel, Murat, Caglayan, Ahmet, Bilguvar, Kaya, Tolun, Aslihan, Issa, Mahmoud Y., Schroth, Jana, Spencer, Emily G., Rosti, Rasim O., Akizu, Naiara, Vaux, Keith K., Johansen, Anide, Koh, Alice A., Megahed, Hisham, Durr, Alexandra, Brice, Alexis, Stevanin, Giovanni, Gabriel, Stacy B., Ideker, Trey, and Gleeson, Joseph G.

Published
2014

9. FOXP1-related intellectual disability syndrome: a recognisable entity

Author

Meerschaut, Ilse, Rochefort, Daniel, Revençu, Nicole, Pètre, Justine, Corsello, Christina, Rouleau, Guy A, Hamdan, Fadi F, Michaud, Jacques L, Morton, Jenny, Radley, Jessica, Ragge, Nicola, García-Miñaúr, Sixto, Lapunzina, Pablo, Bralo, Maria Palomares, Mori, Maria Ángeles, Moortgat, Stéphanie, Benoit, Valérie, Mary, Sandrine, Bockaert, Nele, Oostra, Ann, Vanakker, Olivier, Velinov, Milen, de Ravel, Thomy JL, Mekahli, Djalila, Sebat, Jonathan, Vaux, Keith K, DiDonato, Nataliya, Hanson-Kahn, Andrea K, Hudgins, Louanne, Dallapiccola, Bruno, Novelli, Antonio, Tarani, Luigi, Andrieux, Joris, Parker, Michael J, Neas, Katherine, Ceulemans, Berten, Schoonjans, An-Sofie, Prchalova, Darina, Havlovicova, Marketa, Hancarova, Miroslava, Budisteanu, Magdalena, Dheedene, Annelies, Menten, Björn, Dion, Patrick A, Lederer, Damien, and Callewaert, Bert

Published
2017
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10. Erratum:Biallelic Mutations in ADPRHL2, Encoding ADP-Ribosylhydrolase 3, Lead to a Degenerative Pediatric Stress-Induced Epileptic Ataxia Syndrome (The American Journal of Human Genetics (2018) 103(3) (431–439), (S0002929718302374), (10.1016/j.ajhg.2018.07.010))

Author

Ghosh, Shereen G., Becker, Kerstin, Huang, He, Salazar, Tracy D., Chai, Guoliang, Salpietro, Vincenzo, Al-Gazali, Lihadh, Waisfisz, Quinten, Wang, Haicui, Vaux, Keith K., Stanley, Valentina, Manole, Andreea, Akpulat, Ugur, Weiss, Marjan M., Efthymiou, Stephanie, Hanna, Michael G., Minetti, Carlo, Striano, Pasquale, Pisciotta, Livia, De Grandis, Elisa, Altmüller, Janine, Weixler, Lisa, Nürnberg, Peter, Thiele, Holger, Yis, Uluc, Okur, Tuncay Derya, Polat, Ayse Ipek, Amiri, Nafise, Doosti, Mohammad, Karimani, Ehsan Ghayoor, Toosi, Mehran B., Haddad, Gabriel, Karakaya, Mert, Wirth, Brunhilde, van Hagen, Johanna M., Wolf, Nicole I., Maroofian, Reza, Houlden, Henry, Cirak, Sebahattin, and Gleeson, Joseph G.

Abstract

(The American Journal of Human Genetics 103, 431–439; September 6, 2018) Lisa Weixler has been added to the author list for her experimental and scientific contributions to the biophysical analysis of wild-type and mutant proteins. Her contributions were already mentioned in the acknowledgments. The authors apologize for initially only listing her in the acknowledgments and for the inconvenience. The author list has been corrected online and appears correctly here, and Lisa Weixler's affiliation is indicated as footnote 3: Center for Molecular Medicine Cologne, Cologne, Germany.

Published
2021
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11. Biallelic Mutations in ADPRHL2, Encoding ADP-Ribosylhydrolase 3, Lead to a Degenerative Pediatric Stress-Induced Epileptic Ataxia Syndrome

Author

Ghosh, Shereen G., primary, Becker, Kerstin, additional, Huang, He, additional, Salazar, Tracy D., additional, Chai, Guoliang, additional, Salpietro, Vincenzo, additional, Al-Gazali, Lihadh, additional, Waisfisz, Quinten, additional, Wang, Haicui, additional, Vaux, Keith K., additional, Stanley, Valentina, additional, Manole, Andreea, additional, Akpulat, Ugur, additional, Weiss, Marjan M., additional, Efthymiou, Stephanie, additional, Hanna, Michael G., additional, Minetti, Carlo, additional, Striano, Pasquale, additional, Pisciotta, Livia, additional, De Grandis, Elisa, additional, Altmüller, Janine, additional, Weixler, Lisa, additional, Nürnberg, Peter, additional, Thiele, Holger, additional, Yis, Uluc, additional, Okur, Tuncay Derya, additional, Polat, Ayse Ipek, additional, Amiri, Nafise, additional, Doosti, Mohammad, additional, Karimani, Ehsan Ghayoor, additional, Toosi, Mehran B., additional, Haddad, Gabriel, additional, Karakaya, Mert, additional, Wirth, Brunhilde, additional, van Hagen, Johanna M., additional, Wolf, Nicole I., additional, Maroofian, Reza, additional, Houlden, Henry, additional, Cirak, Sebahattin, additional, and Gleeson, Joseph G., additional

Published
2021
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12. Biallelic Mutations in ADPRHL2, Encoding ADP-Ribosylhydrolase 3, Lead to a Degenerative Pediatric Stress-Induced Epileptic Ataxia Syndrome (vol 103, pg 431, 2018)

Author

Ghosh, Shereen G., Becker, Kerstin, Huang, He, Salazar, Tracy D., Chai, Guoliang, Salpietro, Vincenzo, Al-Gazali, Lihadh, Waisfisz, Quinten, Wang, Haicui, Vaux, Keith K., Stanley, Valentina, Manole, Andreea, Akpulat, Ugur, Weiss, Marjan M., Efthymiou, Stephanie, Hanna, Michael G., Minetti, Carlo, Striano, Pasquale, Pisciotta, Livia, De Grandis, Elisa, Altmuller, Janine, Weixler, Lisa, Nurnberg, Peter, Thiele, Holger, Yis, Uluc, Okur, Tuncay Derya, Polat, Ayse Ipek, Amiri, Nafise, Doosti, Mohammad, Karimani, Ehsan Ghayoor, Toosi, Mehran B., Haddad, Gabriel, Karakaya, Mert, Wirth, Brunhilde, van Hagen, Johanna M., Wolf, Nicole I., Maroofian, Reza, Houlden, Henry, Cirak, Sebahattin, Gleeson, Joseph G., Ghosh, Shereen G., Becker, Kerstin, Huang, He, Salazar, Tracy D., Chai, Guoliang, Salpietro, Vincenzo, Al-Gazali, Lihadh, Waisfisz, Quinten, Wang, Haicui, Vaux, Keith K., Stanley, Valentina, Manole, Andreea, Akpulat, Ugur, Weiss, Marjan M., Efthymiou, Stephanie, Hanna, Michael G., Minetti, Carlo, Striano, Pasquale, Pisciotta, Livia, De Grandis, Elisa, Altmuller, Janine, Weixler, Lisa, Nurnberg, Peter, Thiele, Holger, Yis, Uluc, Okur, Tuncay Derya, Polat, Ayse Ipek, Amiri, Nafise, Doosti, Mohammad, Karimani, Ehsan Ghayoor, Toosi, Mehran B., Haddad, Gabriel, Karakaya, Mert, Wirth, Brunhilde, van Hagen, Johanna M., Wolf, Nicole I., Maroofian, Reza, Houlden, Henry, Cirak, Sebahattin, and Gleeson, Joseph G.

Published
2021

15. Parkes Weber Syndrome, Vein of Galen Aneurysmal Malformation, and Other Fast-Flow Vascular Anomalies Are Caused by RASA1 Mutations

Author

Revencu, Nicole, Boon, Laurence M., Mulliken, John B., Enjolras, Odile, Cordisco, Maria Rosa, Burrows, Patricia E., Clapuyt, Philippe, Hammer, Frank, Dubois, Josée, Baselga, Eulalia, Brancati, Francesco, Carder, Robin, Miguel, José, Quintal, Ceballos, Dallapiccola, Bruno, Fischer, Gayle, Frieden, Ilona J., Garzon, Maria, Harper, John, Johnson-Patel, Jennifer, Labrèze, Christine, Martorell, Loreto, Paltiel, Harriet J., Pohl, Annette, Prendiville, Julie, Quere, Isabelle, Siegel, Dawn H., Valente, Enza Maria, Hagen, Annet Van, Hest, Liselot Van, Vaux, Keith K., Vicente, Asuncion, Weibel, Lisa, Chitayat, David, and Vikkula, Miikka

Published
2008
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16. Biallelic Mutations in ADPRHL2, Encoding ADP-Ribosylhydrolase 3, Lead to a Degenerative Pediatric Stress-Induced Epileptic Ataxia Syndrome

Author

Ghosh, Shereen G., Becker, Kerstin, Huang, He, Salazar, Tracy D., Chai, Guoliang, Salpietro, Vincenzo, Al-Gazali, Lihadh, Waisfisz, Quinten, Wang, Haicui, Vaux, Keith K., Stanley, Valentina, Manole, Andreea, Akpulat, Ugur, Weiss, Marjan M., Efthymiou, Stephanie, Hanna, Michael G., Minetti, Carlo, Striano, Pasquale, Pisciotta, Livia, De Grandis, Elisa, Altmueller, Janine, Nuernberg, Peter, Thiele, Holger, Yis, Uluc, Okur, Tuncay Derya, Polat, Ayse Ipek, Amiri, Nafise, Doosti, Mohammad, Karimani, Ehsan Ghayoor, Toosi, Mehran B., Haddad, Gabriel, Karakaya, Mert, Wirth, Brunhilde, van Hagen, Johanna M., Wolf, Nicole I., Maroofian, Reza, Houlden, Henry, Cirak, Sebahattin, Gleeson, Joseph G., Ghosh, Shereen G., Becker, Kerstin, Huang, He, Salazar, Tracy D., Chai, Guoliang, Salpietro, Vincenzo, Al-Gazali, Lihadh, Waisfisz, Quinten, Wang, Haicui, Vaux, Keith K., Stanley, Valentina, Manole, Andreea, Akpulat, Ugur, Weiss, Marjan M., Efthymiou, Stephanie, Hanna, Michael G., Minetti, Carlo, Striano, Pasquale, Pisciotta, Livia, De Grandis, Elisa, Altmueller, Janine, Nuernberg, Peter, Thiele, Holger, Yis, Uluc, Okur, Tuncay Derya, Polat, Ayse Ipek, Amiri, Nafise, Doosti, Mohammad, Karimani, Ehsan Ghayoor, Toosi, Mehran B., Haddad, Gabriel, Karakaya, Mert, Wirth, Brunhilde, van Hagen, Johanna M., Wolf, Nicole I., Maroofian, Reza, Houlden, Henry, Cirak, Sebahattin, and Gleeson, Joseph G.

Abstract

ADP-ribosylation, the addition of poly-ADP ribose (PAR) onto proteins, is a response signal to cellular challenges, such as excitotoxicity or oxidative stress. This process is catalyzed by a group of enzymes referred to as poly(ADP-ribose) polymerases (PARPs). Because the accumulation of proteins with this modification results in cell death, its negative regulation restores cellular homeostasis: a process mediated by poly-ADP ribose glycohydrolases (PARGs) and ADP-ribosylhydrolase proteins (ARHs). Using linkage analysis and exome or genome sequencing, we identified recessive inactivating mutations in ADPRHL2 in six families. Affected individuals exhibited a pediatric-onset neurodegenerative disorder with progressive brain atrophy, developmental regression, and seizures in association with periods of stress, such as infections. Loss of the Drosophila paralog Parg showed lethality in response to oxidative challenge that was rescued by human ADPRHL2, suggesting functional conservation. Pharmacological inhibition of PARP also rescued the phenotype, suggesting the possibility of postnatal treatment for this genetic condition.

Published
2018

17. Paternally inherited noncoding structural variants contribute to autism

Author

Brandler, William M., primary, Antaki, Danny, additional, Gujral, Madhusudan, additional, Kleiber, Morgan L., additional, Maile, Michelle S., additional, Hong, Oanh, additional, Chapman, Timothy R., additional, Tan, Shirley, additional, Tandon, Prateek, additional, Pang, Timothy, additional, Tang, Shih C., additional, Vaux, Keith K., additional, Yang, Yan, additional, Harrington, Eoghan, additional, Juul, Sissel, additional, Turner, Daniel J., additional, Kingsmore, Stephen F., additional, Gleeson, Joseph G., additional, Kakaradov, Boyko, additional, Telenti, Amalio, additional, Venter, J Craig, additional, Corominas, Roser, additional, Cormand, Bru, additional, Rueda, Isabel, additional, Messer, Karen S., additional, Nievergelt, Caroline M., additional, Arranz, Maria J., additional, Courchesne, Eric, additional, Pierce, Karen, additional, Muotri, Alysson R., additional, Iakoucheva, Lilia M., additional, Hervas, Amaia, additional, Corsello, Christina, additional, and Sebat, Jonathan, additional

Published
2017
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18. FOXP1 -related intellectual disability syndrome: a recognisable entity

Author

UCL - (SLuc) Département de biologie clinique et d'anatomie pathologique, UCL - (SLuc) Centre de génétique médicale UCL, Meerschaut, Ilse, Rochefort, Daniel, Revencu, Nicole, Pètre, Justine, Corsello, Christina, Rouleau, Guy A, Hamdan, Fadi F, Michaud, Jacques L, Morton, Jenny, Radley, Jessica, Ragge, Nicola, García-Miñaúr, Sixto, Lapunzina, Pablo, Bralo, Maria Palomares, Mori, Maria Ángeles, Moortgat, Stéphanie, Benoit, Valérie, Mary, Sandrine, Bockaert, Nele, Oostra, Ann, Vanakker, Olivier, Velinov, Milen, de Ravel, Thomy JL, Mekahli, Djalila, Sebat, Jonathan, Vaux, Keith K, DiDonato, Nataliya, Hanson-Kahn, Andrea K, Hudgins, Louanne, Dallapiccola, Bruno, Novelli, Antonio, Tarani, Luigi, Andrieux, Joris, Parker, Michael J, Neas, Katherine, Ceulemans, Berten, Schoonjans, An-Sofie, Prchalova, Darina, Havlovicova, Marketa, Hancarova, Miroslava, Budisteanu, Magdalena, Dheedene, Annelies, Menten, Björn, Dion, Patrick A, Lederer, Damien, Callewaert, Bert, UCL - (SLuc) Département de biologie clinique et d'anatomie pathologique, UCL - (SLuc) Centre de génétique médicale UCL, Meerschaut, Ilse, Rochefort, Daniel, Revencu, Nicole, Pètre, Justine, Corsello, Christina, Rouleau, Guy A, Hamdan, Fadi F, Michaud, Jacques L, Morton, Jenny, Radley, Jessica, Ragge, Nicola, García-Miñaúr, Sixto, Lapunzina, Pablo, Bralo, Maria Palomares, Mori, Maria Ángeles, Moortgat, Stéphanie, Benoit, Valérie, Mary, Sandrine, Bockaert, Nele, Oostra, Ann, Vanakker, Olivier, Velinov, Milen, de Ravel, Thomy JL, Mekahli, Djalila, Sebat, Jonathan, Vaux, Keith K, DiDonato, Nataliya, Hanson-Kahn, Andrea K, Hudgins, Louanne, Dallapiccola, Bruno, Novelli, Antonio, Tarani, Luigi, Andrieux, Joris, Parker, Michael J, Neas, Katherine, Ceulemans, Berten, Schoonjans, An-Sofie, Prchalova, Darina, Havlovicova, Marketa, Hancarova, Miroslava, Budisteanu, Magdalena, Dheedene, Annelies, Menten, Björn, Dion, Patrick A, Lederer, Damien, and Callewaert, Bert

Abstract

BACKGROUND: Mutations in forkhead box protein P1 (FOXP1) cause intellectual disability (ID) and specific language impairment (SLI), with or without autistic features (MIM: 613670). Despite multiple case reports no specific phenotype emerged so far. METHODS: We correlate clinical and molecular data of 25 novel and 23 previously reported patients with FOXP1 defects. We evaluated FOXP1 activity by an in vitro luciferase model and assessed protein stability in vitro by western blotting. RESULTS: Patients show ID, SLI, neuromotor delay (NMD) and recurrent facial features including a high broad forehead, bent downslanting palpebral fissures, ptosis and/or blepharophimosis and a bulbous nasal tip. Behavioural problems and autistic features are common. Brain, cardiac and urogenital malformations can be associated. More severe ID and NMD, sensorineural hearing loss and feeding difficulties are more common in patients with interstitial 3p deletions (14 patients) versus patients with monogenic FOXP1 defects (34 patients). Mutations result in impaired transcriptional repression and/or reduced protein stability. CONCLUSIONS: FOXP1-related ID syndrome is a recognisable entity with a wide clinical spectrum and frequent systemic involvement. Our data will be helpful to evaluate genotype-phenotype correlations when interpreting next-generation sequencing data obtained in patients with ID and/or SLI and will guide clinical management.

Published
2017

19. Functional genome-wide siRNA screen identifies KIAA0586 as mutated in Joubert syndrome

Author

Roosing, Susanne, Hofree, Matan, Kim, Sehyun, Scott, Eric, Copeland, Brett, Romani, Marta, Silhavy, Jennifer L, Rosti, Rasim O, Schroth, Jana, Mazza, Tommaso, Miccinilli, Elide, Zaki, Maha S, Swoboda, Kathryn J, Milisa-Drautz, Joanne, Dobyns, William B, Mikati, Mohamed A, İncecik, Faruk, Azam, Matloob, Borgatti, Renato, Romaniello, Romina, Boustany, Rose-Mary, Clericuzio, Carol L, D'Arrigo, Stefano, Strømme, Petter, Boltshauser, Eugen, Stanzial, Franco, Mirabelli-Badenier, Marisol, Moroni, Isabella, Bertini, Enrico, Emma, Francesco, Steinlin, Maja, Hildebrandt, Friedhelm, Johnson, Colin A, Freilinger, Michael, Vaux, Keith K, Gabriel, Stacey B, Aza-Blanc, Pedro, Heynen-Genel, Susanne, Ideker, Trey, Dynlacht, Brian D, Lee, Ji Eun, Valente, Enza Maria, Kim, Joon, Gleeson, Joseph G, Roosing, Susanne, Hofree, Matan, Kim, Sehyun, Scott, Eric, Copeland, Brett, Romani, Marta, Silhavy, Jennifer L, Rosti, Rasim O, Schroth, Jana, Mazza, Tommaso, Miccinilli, Elide, Zaki, Maha S, Swoboda, Kathryn J, Milisa-Drautz, Joanne, Dobyns, William B, Mikati, Mohamed A, İncecik, Faruk, Azam, Matloob, Borgatti, Renato, Romaniello, Romina, Boustany, Rose-Mary, Clericuzio, Carol L, D'Arrigo, Stefano, Strømme, Petter, Boltshauser, Eugen, Stanzial, Franco, Mirabelli-Badenier, Marisol, Moroni, Isabella, Bertini, Enrico, Emma, Francesco, Steinlin, Maja, Hildebrandt, Friedhelm, Johnson, Colin A, Freilinger, Michael, Vaux, Keith K, Gabriel, Stacey B, Aza-Blanc, Pedro, Heynen-Genel, Susanne, Ideker, Trey, Dynlacht, Brian D, Lee, Ji Eun, Valente, Enza Maria, Kim, Joon, and Gleeson, Joseph G

Abstract

Defective primary ciliogenesis or cilium stability forms the basis of human ciliopathies, including Joubert syndrome (JS), with defective cerebellar vermis development. We performed a high-content genome-wide small interfering RNA (siRNA) screen to identify genes regulating ciliogenesis as candidates for JS. We analyzed results with a supervised-learning approach, using SYSCILIA gold standard, Cildb3.0, a centriole siRNA screen and the GTex project, identifying 591 likely candidates. Intersection of this data with whole exome results from 145 individuals with unexplained JS identified six families with predominantly compound heterozygous mutations in KIAA0586. A c.428del base deletion in 0.1% of the general population was found in trans with a second mutation in an additional set of 9 of 163 unexplained JS patients. KIAA0586 is an orthologue of chick Talpid3, required for ciliogenesis and Sonic hedgehog signaling. Our results uncover a relatively high frequency cause for JS and contribute a list of candidates for future gene discoveries in ciliopathies.

Published
2015

20. Frequency and complexity of de novo structural mutation in autism

Author

Brandler, William M, primary, Antaki, Danny, additional, Gujral, Madhusudan, additional, Noor, Amina, additional, Rosanio, Gabriel, additional, Chapman, Timothy R, additional, Barrera, Daniel J, additional, Lin, Guan Ning, additional, Malhotra, Dheeraj, additional, Watts, Amanda C, additional, Wong, Lawrence C, additional, Estabillo, Jasper A, additional, Gadomski, Therese E, additional, Hong, Oanh, additional, Fuentes Fajardo, Karin V, additional, Bhandari, Abhishek, additional, Owen, Renius, additional, Baughn, Michael, additional, Yuan, Jeffrey, additional, Solomon, Terry, additional, Moyzis, Alexandra G, additional, Sanders, Stephan J, additional, Reiner, Gail E, additional, Vaux, Keith K, additional, Strom, Charles M, additional, Zhang, Kang, additional, Muotri, Alysson R, additional, Akshoomoff, Natacha, additional, Leal, Suzanne M, additional, Pierce, Karen, additional, Courchesne, Eric, additional, Iakoucheva, Lilia M, additional, Corsello, Christina, additional, and Sebat, Jonathan, additional

Published
2015
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21. Functional genome-wide siRNA screen identifies KIAA0586 as mutated in Joubert syndrome

Author

Roosing, Susanne, primary, Hofree, Matan, additional, Kim, Sehyun, additional, Scott, Eric, additional, Copeland, Brett, additional, Romani, Marta, additional, Silhavy, Jennifer L, additional, Rosti, Rasim O, additional, Schroth, Jana, additional, Mazza, Tommaso, additional, Miccinilli, Elide, additional, Zaki, Maha S, additional, Swoboda, Kathryn J, additional, Milisa-Drautz, Joanne, additional, Dobyns, William B, additional, Mikati, Mohamed A, additional, İncecik, Faruk, additional, Azam, Matloob, additional, Borgatti, Renato, additional, Romaniello, Romina, additional, Boustany, Rose-Mary, additional, Clericuzio, Carol L, additional, D'Arrigo, Stefano, additional, Strømme, Petter, additional, Boltshauser, Eugen, additional, Stanzial, Franco, additional, Mirabelli-Badenier, Marisol, additional, Moroni, Isabella, additional, Bertini, Enrico, additional, Emma, Francesco, additional, Steinlin, Maja, additional, Hildebrandt, Friedhelm, additional, Johnson, Colin A, additional, Freilinger, Michael, additional, Vaux, Keith K, additional, Gabriel, Stacey B, additional, Aza-Blanc, Pedro, additional, Heynen-Genel, Susanne, additional, Ideker, Trey, additional, Dynlacht, Brian D, additional, Lee, Ji Eun, additional, Valente, Enza Maria, additional, Kim, Joon, additional, and Gleeson, Joseph G, additional

Published
2015
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22. Author response: Functional genome-wide siRNA screen identifies KIAA0586 as mutated in Joubert syndrome

Author

Roosing, Susanne, primary, Hofree, Matan, additional, Kim, Sehyun, additional, Scott, Eric, additional, Copeland, Brett, additional, Romani, Marta, additional, Silhavy, Jennifer L, additional, Rosti, Rasim O, additional, Schroth, Jana, additional, Mazza, Tommaso, additional, Miccinilli, Elide, additional, Zaki, Maha S, additional, Swoboda, Kathryn J, additional, Milisa-Drautz, Joanne, additional, Dobyns, William B, additional, Mikati, Mohamed A, additional, İncecik, Faruk, additional, Azam, Matloob, additional, Borgatti, Renato, additional, Romaniello, Romina, additional, Boustany, Rose-Mary, additional, Clericuzio, Carol L, additional, D'Arrigo, Stefano, additional, Strømme, Petter, additional, Boltshauser, Eugen, additional, Stanzial, Franco, additional, Mirabelli-Badenier, Marisol, additional, Moroni, Isabella, additional, Bertini, Enrico, additional, Emma, Francesco, additional, Steinlin, Maja, additional, Hildebrandt, Friedhelm, additional, Johnson, Colin A, additional, Freilinger, Michael, additional, Vaux, Keith K, additional, Gabriel, Stacey B, additional, Aza-Blanc, Pedro, additional, Heynen-Genel, Susanne, additional, Ideker, Trey, additional, Dynlacht, Brian D, additional, Lee, Ji Eun, additional, Valente, Enza Maria, additional, Kim, Joon, additional, and Gleeson, Joseph G, additional

Published
2015
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23. Inactivating mutations in MFSD2A, required for omega-3 fatty acid transport in brain, cause a lethal microcephaly syndrome

Author

Guemez-Gamboa, Alicia, primary, Nguyen, Long N, additional, Yang, Hongbo, additional, Zaki, Maha S, additional, Kara, Majdi, additional, Ben-Omran, Tawfeg, additional, Akizu, Naiara, additional, Rosti, Rasim Ozgur, additional, Rosti, Basak, additional, Scott, Eric, additional, Schroth, Jana, additional, Copeland, Brett, additional, Vaux, Keith K, additional, Cazenave-Gassiot, Amaury, additional, Quek, Debra Q Y, additional, Wong, Bernice H, additional, Tan, Bryan C, additional, Wenk, Markus R, additional, Gunel, Murat, additional, Gabriel, Stacey, additional, Chi, Neil C, additional, Silver, David L, additional, and Gleeson, Joseph G, additional

Published
2015
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25. Parkes Weber syndrome, vein of Galen aneurysmal malformation, and other fast-flow vascular anomalies are caused by RASA1 mutations

Author

UCL - (SLuc) Service de chirurgie plastique, UCL - (SLuc) Centre de malformations vasculaires congénitales, UCL - (SLuc) Centre de génétique médicale UCL, UCL - (SLuc) Service de radiologie, UCL - MD/RAIM - Département de radiologie et d'imagerie médicale, Revencu, Nicole, Boon, Laurence M., Mulliken, John B, Enjolras, Odile, Cordisco, Maria Rosa, Burrows, Patricia E, Clapuyt, Philippe, Hammer, Frank, Dubois, Josée, Baselga, Eulalia, Brancati, Francesco, Carder, Robin, Quintal, José Miguel Ceballos, Dallapiccola, Bruno, Fischer, Gayle, Frieden, Ilona J, Garzon, Maria, Harper, John, Johnson-Patel, Jennifer, Labrèze, Christine, Martorell, Loreto, Paltiel, Harriet J, Pohl, Annette, Prendiville, Julie, Quere, Isabelle, Siegel, Dawn H, Valente, Enza Maria, Van Hagen, Annet, Van Hest, Liselot, Vaux, Keith K, Vicente, Asuncion, Weibel, Lisa, Chitayat, David, Vikkula, Miikka, UCL - (SLuc) Service de chirurgie plastique, UCL - (SLuc) Centre de malformations vasculaires congénitales, UCL - (SLuc) Centre de génétique médicale UCL, UCL - (SLuc) Service de radiologie, UCL - MD/RAIM - Département de radiologie et d'imagerie médicale, Revencu, Nicole, Boon, Laurence M., Mulliken, John B, Enjolras, Odile, Cordisco, Maria Rosa, Burrows, Patricia E, Clapuyt, Philippe, Hammer, Frank, Dubois, Josée, Baselga, Eulalia, Brancati, Francesco, Carder, Robin, Quintal, José Miguel Ceballos, Dallapiccola, Bruno, Fischer, Gayle, Frieden, Ilona J, Garzon, Maria, Harper, John, Johnson-Patel, Jennifer, Labrèze, Christine, Martorell, Loreto, Paltiel, Harriet J, Pohl, Annette, Prendiville, Julie, Quere, Isabelle, Siegel, Dawn H, Valente, Enza Maria, Van Hagen, Annet, Van Hest, Liselot, Vaux, Keith K, Vicente, Asuncion, Weibel, Lisa, Chitayat, David, and Vikkula, Miikka

Abstract

Capillary malformation-arteriovenous malformation (CM-AVM) is a newly recognized autosomal dominant disorder, caused by mutations in the RASA1 gene in six families. Here we report 42 novel RASA1 mutations and the associated phenotype in 44 families. The penetrance and de novo occurrence were high. All affected individuals presented multifocal capillary malformations (CMs), which represent the hallmark of the disorder. Importantly, one-third had fast-flow vascular lesions. Among them, we observed severe intracranial AVMs, including vein of Galen aneurysmal malformation, which were symptomatic at birth or during infancy, extracranial AVM of the face and extremities, and Parkes Weber syndrome (PKWS), previously considered sporadic and nongenetic. These fast-flow lesions can be differed from the other two genetic AVMs seen in hereditary hemorrhagic telangiectasia (HHT) and in phosphatase and tensin homolog (PTEN) hamartomatous tumor syndrome. Finally, some CM-AVM patients had neural tumors reminiscent of neurofibromatosis type 1 or 2. This is the first extensive study on the phenotypes associated with RASA1 mutations, and unravels their wide heterogeneity.

Published
2008

27. Evidence-Based Recommendations for the Diagnosis and Treatment of Pediatric Acne

Author

Eichenfield, Lawrence F., primary, Krakowski, Andrew C., additional, Piggott, Caroline, additional, Del Rosso, James, additional, Baldwin, Hilary, additional, Friedlander, Sheila Fallon, additional, Levy, Moise, additional, Lucky, Anne, additional, Mancini, Anthony J., additional, Orlow, Seth J., additional, Yan, Albert C., additional, Vaux, Keith K., additional, Webster, Guy, additional, Zaenglein, Andrea L., additional, and Thiboutot, Diane M., additional

Published
2013
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30. Parkes Weber syndrome, vein of Galen aneurysmal malformation, and other fast-flow vascular anomalies are caused byRASA1 mutations

Author

Revencu, Nicole, primary, Boon, Laurence M., additional, Mulliken, John B., additional, Enjolras, Odile, additional, Cordisco, Maria Rosa, additional, Burrows, Patricia E., additional, Clapuyt, Philippe, additional, Hammer, Frank, additional, Dubois, Josée, additional, Baselga, Eulalia, additional, Brancati, Francesco, additional, Carder, Robin, additional, Quintal, José Miguel Ceballos, additional, Dallapiccola, Bruno, additional, Fischer, Gayle, additional, Frieden, Ilona J., additional, Garzon, Maria, additional, Harper, John, additional, Johnson-Patel, Jennifer, additional, Labrèze, Christine, additional, Martorell, Loreto, additional, Paltiel, Harriet J., additional, Pohl, Annette, additional, Prendiville, Julie, additional, Quere, Isabelle, additional, Siegel, Dawn H., additional, Valente, Enza Maria, additional, Van Hagen, Annet, additional, Van Hest, Liselot, additional, Vaux, Keith K., additional, Vicente, Asuncion, additional, Weibel, Lisa, additional, Chitayat, David, additional, and Vikkula, Miikka, additional

Published
2008
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32. Neonatal phenotype in Kabuki syndrome

Author

Vaux, Keith K., primary, Hudgins, Louanne, additional, Bird, Lynne M., additional, Roeder, Elizabeth, additional, Curry, Cynthia J.R., additional, Jones, Marilyn, additional, and Jones, Kenneth L., additional

Published
2004
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41. Neonatal phenotype in Kabuki syndrome

Author

Vaux, Keith K., Hudgins, Louanne, Bird, Lynne M., Roeder, Elizabeth, Curry, Cynthia J.R., Jones, Marilyn, and Jones, Kenneth L.

Abstract

The Kabuki syndrome is a well‐established pattern of human malformation with readily recognizable features, however the diagnosis is rarely made in the newborn period. The purpose of this study was to determine if there exists a neonatal phenotype for this disorder. We ascertained 16 infants evaluated in the first 28 days of life by a dysmorphologist who subsequently received the diagnosis of Kabuki syndrome. The average age of initial evaluation was 8 days and the average age of diagnosis was 2 years 6 months. Based on these findings, it is suggested that the distinctive clinical phenotype seen in older patients is also evident in the newborn period. Published 2004 Wiley‐Liss, Inc.

Published
2005
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42. Megalourethra: A report of three cases associated with maternal diabetes and a review of the literature—is sonic hedgehog the common pathway?

Author

Vaux, Keith K., Jones, Marilyn C., Benirschke, Kurt, Bird, Lynne M., and Jones, Kenneth L.

Abstract

The mechanisms by which maternal diabetes causes malformations in the offspring have yet to be elucidated. The purpose of this report is twofold: first, to describe three male infants born with multiple congenital anomalies and megalourethra, a defect which has not been previously reported in infants of women with diabetes; and second, to indicate that the defects seen in association with megalourethra in these three infants are similar to those seen as a consequence of abnormalities in sonic hedgehog, suggesting that maternal diabetes may affect sonic hedgehog expression in susceptible tissues during critical stages of development. Published 2004 Wiley‐Liss, Inc.

Published
2005
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43. Developmental outcome in Kabuki syndrome

Author

Vaux, Keith K., Jones, Kenneth L., Jones, Marilyn C., Schelley, Susan, and Hudgins, Louanne

Abstract

Over the last 20 years, a wide spectrum of congenital anomalies have been described in association with Kabuki syndrome (KS). However, very little information is available on developmental outcome. As more individuals with this syndrome are recognized and reported, it appears that as many as one‐sixth may have normal intelligence. The purpose of this report is to describe the developmental outcome in 15 patients with KS, to determine whether a recognizable pattern of disabilities exist, and whether developmental outcome correlates with the presence of malformations. We ascertained 15 patients with KS from three dysmorphology and clinical genetics services in which developmental milestones and formal developmental testing were available. Based on these patients and a review of the literature, in the absence of major structural brain anomalies, the average intelligence quotient (IQ) in patients with this condition fall within the mild mental retardation range, however, specific developmental outcomes are widely variable, ranging from severe MR to normal intelligence. The presence or absence of hearing loss or major malformations, other than those involving the brain, was not predictive of developmental outcome. Published 2004 Wiley‐Liss, Inc.

Published
2005
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45. Biallelic mutations in SNX14 cause a syndromic form of cerebellar atrophy and lysosome-autophagosome dysfunction

Author

Keith K. Vaux, Mahmut Şamil Sağıroğlu, Laila Bastaki, Seth J. Field, Pascale de Lonlay, Sawsan Abdel-Hadi, Lihadh Al-Gazali, Hülya Kayserili, Ali Dursun, Jeffrey D. Esko, Eric Scott, Xin Wang, Faezeh Mojahedi, Ashleigh E. Schaffer, R. Köksal Özgül, Iman G. Mahmoud, Isabelle Desguerre, Matthew D. Buschman, Laila Selim, Samia A. Temtamy, Jean-Laurent Casanova, Murat Gunel, Abdelrahim Abdrabou Sadek, Philip L.S.M. Gordts, Brett Copeland, Mona Aglan, Amira Masri, Maha S. Zaki, Joseph G. Gleeson, Matloob Azam, Naiara Akizu, Vincent Cantagrel, Antoinette Gelot, Basak Rosti, Jennifer L. Silhavy, Esra Dikoglu, Ulrich Müller, Amera El Badawy, Gennaro Napolitano, Stacey Gabriel, Rasim Ozgur Rosti, Jana Schroth, Samira Ismail, Ghada M H Abdel-Salam, İç Hastalıkları, Akizu, Naiara, Cantagrel, Vincent, Zaki, Maha S., Al-Gazali, Lihadh, Wang, Xin, Rosti, Rasim Ozgur, Dikoglu, Esra, Gelot, Antoinette Bernabe, Rosti, Basak, Vaux, Keith K., Scott, Eric M., Silhavy, Jennifer L., Schroth, Jana, Copeland, Brett, Schaffer, Ashleigh E., Gordts, Philip L. S. M., Esko, Jeffrey D., Buschman, Matthew D., Field, Seth J., Napolitano, Gennaro, Abdel-Salam, Ghada M., Ozgul, R Koksal, Saglroglu, Mahmut Samil, Azam, Matloob, Ismail, Samira, Aglan, Mona, Selim, Laila, Mahmoud, Iman G., Abdel-Hadi, Sawsan, Badawy, Amera El, Sadek, Abdelrahim A., Mojahedi, Faezeh, Kayserili, Hulya, Masri, Amira, Bastaki, Laila, Temtamy, Samia, Müller, Ulrich, Desguerre, Isabelle, Casanova, Jean-Laurent, Dursun, Ali, Gunel, Murat, Gabriel, Stacey B., De Lonlay, Pascale, and Gleeson, Joseph G.

Subjects
Male, Autophagosome, medicine.disease_cause, Medical and Health Sciences, Lysosomal Storage Disease, Gene Frequency, Cerebellum, Phagosomes, Child, Sorting Nexins, Phagosome, Zebrafish, 2. Zero hunger, Genetics, Mutation, Cerebellar Disease, Syndrome, Biological Sciences, Lysosome, Cell biology, medicine.anatomical_structure, Child, Preschool, Female, Cerebellar atrophy, medicine.symptom, Human, Ataxia, Endosome, Biology, Article, Cerebellar Diseases, Clinical Research, Autophagy, medicine, Animals, Humans, Spinocerebellar Ataxias, Preschool, Spinocerebellar Ataxia, Animal, Sorting Nexin, Infant, Brain Disorders, Lysosomal Storage Diseases, Sorting nexin, Atrophy, Lod Score, Lysosomes, Developmental Biology
Abstract

Pediatric-onset ataxias often present clinically as developmental delay and intellectual disability, with prominent cerebellar atrophy as a key neuroradiographic finding. Here we describe a new clinically distinguishable recessive syndrome in 12 families with cerebellar atrophy together with ataxia, coarsened facial features and intellectual disability, due to truncating mutations in the sorting nexin gene SNX14, encoding a ubiquitously expressed modular PX domain-containing sorting factor. We found SNX14 localized to lysosomes and associated with phosphatidylinositol (3,5)-bisphosphate, a key component of late endosomes/lysosomes. Patient-derived cells showed engorged lysosomes and a slower autophagosome clearance rate upon autophagy induction by starvation. Zebrafish morphants for snx14 showed dramatic loss of cerebellar parenchyma, accumulation of autophagosomes and activation of apoptosis. Our results characterize a unique ataxia syndrome due to biallelic SNX14 mutations leading to lysosome-autophagosome dysfunction.

Published
2015
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