Author:
Blackburn Alexandria T.M.,Bekheirnia Nasim,C. Uma Vanessa,Rosenfeld Jill A.,Bainbridge Matthew N.,Yang Yaping,Liu Pengfei,Madan-Khetarpal Suneeta,Delgado Mauricio R.,Hudgins Louanne,Krantz Ian,Rodriguez-Buritica David,G. Wheeler Patricia,Gazali Lihadh Al,Mohamed Al Shamsi Aisha Mohamed Saeed,Gomez-Ospina Natalia,Chao Hsiao-Tuan,Mirzaa Ghayda M.,Scheuerle Angela E.,Kukolich Mary K,Scaglia Fernando,Eng Christine,Braun Michael C.,Lamb Dolores J.,Miller Rachel K.,Bekheirnia Mir Reza
Abstract
ABSTRACTPurposeHaploinsufficiency 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.
Publisher
Cold Spring Harbor Laboratory