Mutations in DDX3X Are a Common Cause of Unexplained Intellectual Disability with Gender-Specific Effects on Wnt Signaling
| Autor: | Tjitske Kleefstra, Katherine G. Keating, Marie Shaw, Lisenka E.L.M. Vissers, Sascha Vermeer, Jane Juusola, Barbara K. Burton, Margaret H. Harr, Hanka Venselaar, Kevin A. Strauss, Angela Myers, Antonie D. Kline, Karlla W. Brigatti, Koen L.I. van Gassen, Wendy K. Chung, E. Smeets, Willemijn M. Wissink-Lindhout, Usha Kini, Katrina Tatton-Brown, Alexander Hoischen, Amy S. Kimball, C Jensen, Hilde Van Esch, Christian Gilissen, Maaike Vreeburg, Patrick Reed, Perciliz L. Tan, M Bienek, Diana Baralle, Julie McLaughlin, Joyce Fox, Stefan A. Haas, Nicholas Katsanis, Tom S. Koemans, Jolanda H. Schieving, Janneke H M Schuurs-Hoeijmakers, Jennifer Norman, Vera M. Kalscheuer, Sally Ann Lynch, Sarju G. Mehta, Anke Van Dijck, Megan T. Cho, Alison Male, Erik C. Madsen, Katrina Haude, Marvin R. Natowicz, Pradeep Vasudevan, Jacques C. Giltay, Kyle Retterer, Alison Ross, Kristin Lindstrom, Han G. Brunner, Katherine H. Kim, Michael Parker, A. Micheil Innes, Bart Loeys, R. Frank Kooy, Joel Charrow, Kristin G. Monaghan, Eric Haan, Michael C. Kruer, Margot R.F. Reijnders, Andreas Rump, Rolph Pfundt, Lot Snijders Blok, Quinn Stein, Jozef Gecz, Audrey Foster-Barber, Elaine H. Zackai, Karin Oberndorff, Kees E. P. van Roozendaal, Alan Fryer, Ruth Newbury-Ecob, Nataliya Di Donato, Kate Chandler, Alex Henderson, Céline Helsmoortel, Igor Pediaditakis, Bregje W.M. van Bon, Eden Haverfield, Corrado Romano, Sybe Dijkstra, Evan E. Eichler, Connie T.R.M. Stumpel, Hilary Racher |
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| Přispěvatelé: | DDD Study, RS: GROW - Developmental Biology, MUMC+: DA KG Polikliniek (9), MUMC+: DA KG Lab Centraal Lab (9), MUMC+: DA Klinische Genetica (5), RS: GROW - R4 - Reproductive and Perinatal Medicine |
| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Male
Embryo Nonmammalian Gene Dosage Case Reports Bioinformatics medicine.disease_cause Medical and Health Sciences BETA-CATENIN DEAD-box RNA Helicases 5. Gender equality 2.1 Biological and endogenous factors Missense mutation Exome Genetics(clinical) HUMAN Y-CHROMOSOME Aetiology 10. No inequality Non-U.S. Gov't Wnt Signaling Pathway Zebrafish Genetics (clinical) X chromosome Exome sequencing Genetics & Heredity Genetics Mutation Sex Characteristics WNT/BETA-CATENIN Nonmammalian Research Support Non-U.S. Gov't Biological Sciences Hypotonia Phenotype DOMINANT DIFFERENTIATION Embryo Female medicine.symptom Sequence Analysis Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] Intellectual and Developmental Disabilities (IDD) Molecular Sequence Data Mutation Missense Context (language use) Other Research Radboud Institute for Molecular Life Sciences [Radboudumc 0] Biology Research Support X-inactivation N.I.H Research Support N.I.H. Extramural X-CHROMOSOME INACTIVATION Clinical Research Intellectual Disability Report medicine Journal Article Animals Humans NEURECTODERM DDD Study Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] Base Sequence ZEBRAFISH Human Genome Extramural DNA Sequence Analysis DNA Brain Disorders Amino Acid Substitution RNA Human medicine Missense Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19] MENTAL-RETARDATION |
| Zdroj: | The American journal of human genetics American Journal of Human Genetics, 97, 2, pp. 343-52 American Journal of Human Genetics, 97(2), 343. Cell Press American Journal of Human Genetics, 97(2), 343-352. Cell Press Europe PubMed Central The American Journal of Human Genetics American Journal of Human Genetics, 97, 343-52 American Journal of Human Genetics, 97(2), 343-352. CELL PRESS American journal of human genetics, vol 97, iss 2 |
| ISSN: | 0002-9297 |
| Popis: | Contains fulltext : 153453.pdf (Publisher’s version ) (Open Access) Intellectual disability (ID) affects approximately 1%-3% of humans with a gender bias toward males. Previous studies have identified mutations in more than 100 genes on the X chromosome in males with ID, but there is less evidence for de novo mutations on the X chromosome causing ID in females. In this study we present 35 unique deleterious de novo mutations in DDX3X identified by whole exome sequencing in 38 females with ID and various other features including hypotonia, movement disorders, behavior problems, corpus callosum hypoplasia, and epilepsy. Based on our findings, mutations in DDX3X are one of the more common causes of ID, accounting for 1%-3% of unexplained ID in females. Although no de novo DDX3X mutations were identified in males, we present three families with segregating missense mutations in DDX3X, suggestive of an X-linked recessive inheritance pattern. In these families, all males with the DDX3X variant had ID, whereas carrier females were unaffected. To explore the pathogenic mechanisms accounting for the differences in disease transmission and phenotype between affected females and affected males with DDX3X missense variants, we used canonical Wnt defects in zebrafish as a surrogate measure of DDX3X function in vivo. We demonstrate a consistent loss-of-function effect of all tested de novo mutations on the Wnt pathway, and we further show a differential effect by gender. The differential activity possibly reflects a dose-dependent effect of DDX3X expression in the context of functional mosaic females versus one-copy males, which reflects the complex biological nature of DDX3X mutations. |
| Databáze: | OpenAIRE |
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