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DYRK1A-related intellectual disability: a syndrome associated with congenital anomalies of the kidney and urinary tract

Blackburn A, Bekheirnia N, Uma VC, Rosenfeld JA, Bainbridge MN, Yang Y, Liu P, Madan-Khetarpal S, Delgado MR, Hudgins L, Ian Krantz I, Rodriguez-Buritica D, Wheeler PG, Al Gazali L, Al Shamsi AMSM, Gomez-Ospina N, Chao H-T, Mirzaa GM, Scheuerle AE, Kukolich MK, Scaglia F, Eng C, Braun MC, Lamb DJ, Miller RK, Bekheirnia MR
bioRxiv. 2019;[Preprint] doi:10.1101/516856
Purpose: Haploinsufficiency 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. Methods: A 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. Results: Phenotypic 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. Conclusion: Evidence 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. Keywords: CAKUT, exome sequencing, DYRK1A, Xenopus, intellectual disability
Organism or Cell Type: 
Xenopus laevis
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