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
DOI: 10.1038/s41431-019-0370-0
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
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