DYRK1A-related intellectual disability: a syndrome associated with congenital anomalies of the kidney and urinary tract
| Autor: | Mir Reza Bekheirnia, Ian D. Krantz, Suneeta Madan-Khetarpal, David Rodriguez-Buritica, Lihadh Al-Gazali, Louanne Hudgins, Hsiao-Tuan Chao, Rachel K. Miller, Matthew N. Bainbridge, Christine M. Eng, Fernando Scaglia, Patricia G. Wheeler, Mary K. Kukolich, Ghayda M. Mirzaa, Michael C. Braun, Natalia Gomez-Ospina, Alexandria T.M. Blackburn, Nasim Bekheirnia, Yaping Yang, Vanessa C. Uma, Mauricio R. Delgado, Angela E. Scheuerle, Dolores J. Lamb, Jill A. Rosenfeld, Pengfei Liu, Aisha Al Shamsi |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0303 health sciences
biology ved/biology business.industry Genitourinary system Urinary system ved/biology.organism_classification_rank.species Xenopus Bioinformatics biology.organism_classification Phenotype 03 medical and health sciences 0302 clinical medicine Medicine Haploinsufficiency Model organism business 030217 neurology & neurosurgery Loss function Exome sequencing 030304 developmental biology |
| DOI: | 10.1101/516856 |
| Popis: | PurposeHaploinsufficiency of DYRK1A causes a recognizable clinical syndrome. The goal of this paper is to investigate congenital anomalies of the kidney and urinary tract (CAKUT) and genital defects (GD) in patients with DYRK1A mutations.MethodsA large database of clinical exome sequencing (ES) was queried for de novo DYRK1A mutations and CAKUT/GD phenotypes were characterized. Xenopus laevis (frog) was chosen as a model organism to assess Dyrk1a’s role in renal development.ResultsPhenotypic details and mutations of 19 patients were compiled after an initial observation that one patient with a de novo pathogenic mutation in DYRK1A had GD. CAKUT/GD data were available from 15 patients, 11 of whom present with CAKUT/GD. Studies in Xenopus embryos demonstrate that knockdown of Dyrk1a disrupts the development of segments of developing embryonic nephrons, which ultimately give rise to the entire genitourinary (GU) tract. These defects could be rescued by co-injecting wildtype human DYRK1A RNA, but not with truncated DYRK1AR205* RNA.ConclusionEvidence supports routine GU screening of all individuals with de novo DYRK1A pathogenic variants to ensure optimized clinical management. Collectively, the reported clinical data and loss of function studies in Xenopus substantiate a novel role for DYRK1A in GU development. |
| Databáze: | OpenAIRE |
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