DYRK1A-related intellectual disability: a syndrome associated with congenital anomalies of the kidney and urinary tract
| Autor: | Jill A. Rosenfeld, Mir Reza Bekheirnia, Ian D. Krantz, Suneeta Madan-Khetarpal, Angela E. Scheuerle, Dolores J. Lamb, David Rodriguez-Buritica, Nasim Bekheirnia, Aisha Al Shamsi, Yaping Yang, Ghayda M. Mirzaa, Yuxiao Xu, Rachel K. Miller, Mauricio R. Delgado, Patricia G. Wheeler, Matthew N. Bainbridge, Natalia Gomez-Ospina, Helen Rankin Willsey, Mark E. Corkins, Alexandria T.M. Blackburn, Lihadh Al-Gazali, Michael C. Braun, Pengfei Liu, Vanessa C. Uma, Mary K. Kukolich, Louanne Hudgins, Hsiao-Tuan Chao, Fernando Scaglia, Christine M. Eng |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Adult Male DYRK1A Adolescent Urinary system Xenopus ved/biology.organism_classification_rank.species Haploinsufficiency 030105 genetics & heredity Protein Serine-Threonine Kinases Bioinformatics Kidney Article 03 medical and health sciences Xenopus laevis Young Adult Intellectual Disability Databases Genetic Exome Sequencing medicine Animals Humans Exome Model organism Child Urinary Tract Genetics (clinical) Exome sequencing CAKUT Genitourinary system ved/biology business.industry Nephrons Protein-Tyrosine Kinases Phenotype 3. Good health Disease Models Animal 030104 developmental biology medicine.anatomical_structure Child Preschool Urogenital Abnormalities Female business |
| Zdroj: | Genetics in medicine : official journal of the American College of Medical Genetics |
| ISSN: | 1530-0366 |
| Popis: | 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 variants. Methods: 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. Results: 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 present with CAKUT/GD. Studies in Xenopus embryos demonstrate 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 co-injecting wild-type human DYRK1A RNA, but not with DYRK1AR205* or DYRK1AL245R 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. |
| Databáze: | OpenAIRE |
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