Deletions and loss-of-function variants in TP63 associated with orofacial clefting
| Autor: | Kaare Christensen, Marie José H. Van Den Boogaard, Volker Dötsch, Ozan Topaloglu, Alexander Hoischen, Kriti D. Khandelwal, Jakob Gebel, Ellen van Beusekom, Nel Roeleveld, Elisabeth Mangold, Sarah L. Mehrem, Christian Gilissen, Joseph Schoenaers, Koen Devriendt, Greet Hens, Stefaan J. Bergé, Iris A.L.M. van Rooij, Jeffrey C. Murray, Hans van Bokhoven, Marloes Steehouwer, Carine Carels, Kerstin U. Ludwig, Ellen van Binsbergen, Nina Ishorst, Christina Fagerberg, Huiqing Zhou |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Adult
Male Cleft Lip Population lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4] Mutation Missense Biology Article Healthcare improvement science Radboud Institute for Health Sciences [Radboudumc 18] Frameshift mutation Cohort Studies 03 medical and health sciences Loss of Function Mutation TP63 Genetics Humans Missense mutation Genetics(clinical) Copy-number variation Allele education Alleles Genetics (clinical) Loss function Sequence Deletion 0303 health sciences education.field_of_study Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] Base Sequence Tumor Suppressor Proteins 030305 genetics & heredity Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6] Middle Aged Penetrance Reconstructive and regenerative medicine Radboud Institute for Health Sciences [Radboudumc 10] Cleft Palate Reconstructive and regenerative medicine Radboud Institute for Molecular Life Sciences [Radboudumc 10] Amino Acid Substitution Female Molecular Developmental Biology Transcription Factors |
| Zdroj: | Eur J Hum Genet European Journal of Human Genetics, 27, 7, pp. 1101-1112 European Journal of Human Genetics, 27(7), 1101. Nature Publishing Group European Journal of Human Genetics, 27, 1101-1112 Khandelwal, K D, van den Boogaard, M-J H, Mehrem, S L, Gebel, J, Fagerberg, C, van Beusekom, E, van Binsbergen, E, Topaloglu, O, Steehouwer, M, Gilissen, C, Ishorst, N, van Rooij, I A L M, Roeleveld, N, Christensen, K, Schoenaers, J, Bergé, S, Murray, J C, Hens, G, Devriendt, K, Ludwig, K U, Mangold, E, Hoischen, A, Zhou, H, Dötsch, V, Carels, C E L & van Bokhoven, H 2019, ' Deletions and loss-of-function variants in TP63 associated with orofacial clefting ', European Journal of Human Genetics, vol. 27, no. 7, pp. 1101-1112 . https://doi.org/10.1038/s41431-019-0370-0 |
| ISSN: | 1476-5438 1018-4813 |
| Popis: | Contains fulltext : 204872.pdf (Publisher’s version ) (Open Access) We aimed to identify novel deletions and variants of TP63 associated with orofacial clefting (OFC). Copy number variants were assessed in three OFC families using microarray analysis. Subsequently, we analyzed TP63 in a cohort of 1072 individuals affected with OFC and 706 population-based controls using molecular inversion probes (MIPs). We identified partial deletions of TP63 in individuals from three families affected with OFC. In the OFC cohort, we identified several TP63 variants predicting to cause loss-of-function alleles, including a frameshift variant c.569_576del (p.(Ala190Aspfs*5)) and a nonsense variant c.997C>T (p.(Gln333*)) that introduces a premature stop codon in the DNA-binding domain. In addition, we identified the first missense variants in the oligomerization domain c.1213G>A (p.(Val405Met)), which occurred in individuals with OFC. This variant was shown to abrogate oligomerization of mutant p63 protein into oligomeric complexes, and therefore likely represents a loss-of-function allele rather than a dominant-negative. All of these variants were inherited from an unaffected parent, suggesting reduced penetrance of such loss-of-function alleles. Our data indicate that loss-of-function alleles in TP63 can also give rise to OFC as the main phenotype. We have uncovered the dosage-dependent functions of p63, which were previously rejected. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink