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 variants.
A large database of clinical exome sequencing (ES) was queried for de novo DYRK1A variants and CAKUT/GD phenotypes were characterized. Xenopus laevis (frog) was chosen as a model organism to assess Dyrk1a’s role in renal development.
Phenotypic details and variants of 19 patients were compiled after an initial observation that one patient with a de novo pathogenic variant in DYRK1A had GD. CAKUT/GD data were available from 15 patients, 11 of whom presented with CAKUT/GD. Studies in Xenopus embryos demonstrated that knockdown of Dyrk1a, which is expressed in forming nephrons, disrupts the development of segments of embryonic nephrons, which ultimately give rise to the entire genitourinary (GU) tract. These defects could be rescued by coinjecting wild-type human DYRK1A RNA, but not with DYRK1AR205* or DYRK1AL245R RNA.
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.
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We express our sincere gratitude to the patients and their families for their participation in this study. The human studies were supported in part by K12 DK0083014 Multidisciplinary K12 Urologic Research Career Development Program, R01DK078121 from the National Institute of Diabetes and Digestive and Kidney Diseases awarded to D.J.L., startup funding from the Department of Pediatrics (Renal Section to M.R.B.), and the Wood Family Foundation. We appreciate all the efforts by BG diagnostic laboratory faculty and staff. Xenopus studies were supported by National Institute of Diabetes and Digestive and Kidney Diseases grants (K01DK092320, R03DK118771 and R01 DK115655 to R.K.M.) and startup funding from the Department of Pediatrics, Pediatric Research Center at the McGovern Medical School (to R.K.M.). Xenopus gene expression studies were also generously supported by Matthew W. State (University of California–San Francisco [UCSF]) and Richard M. Harland (UC Berkeley) and through National Institute of Mental Health grants (U01 MH115747-01A1 to M.W.S. and 1R21MH112158-01 to R.M.H.). We thank the instructors and teaching assistants of the 2017 Cold Spring Harbor Laboratory Xenopus course, in particular K.J. Liu and M.K. Khokha. We are grateful to the members of the laboratories of R.K. Miller and P.D. McCrea, as well as to M. Kloc, for their helpful suggestions and advice throughout this project. In particular, we thank H. Ji and P.D. McCrea for valuable constructs. J.C. Whitney and T.H. Gomez who took care of the animals, even during Hurricane Harvey. We are grateful to the UTHealth Office of the Executive Vice President and Chief Academic Officer and the Department of Pediatrics Microscopy Core for funding the Zeiss LSM800 confocal microscope used in this work. Research reported in this publication was partially supported by the National Institute of Neurological Disorders and Stroke (NINDS) under award number K08NS092898 and Jordan’s Guardian Angels (to G.M.M.).
The Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from clinical exome sequencing offered by the Baylor Genetics Laboratories. Authors who are faculty members in the Department of Molecular and Human Genetics at Baylor College of Medicine are identified as such in the affiliation section. M.N.B. is the founder of Codified Genomics LLC, a genomic interpretation company. The other authors declare no conflicts of interest.
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