ABSTRACT
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ABSTRACT
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 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. 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.
Subject(s)
Intellectual Disability/genetics , Protein Serine-Threonine Kinases/genetics , Protein-Tyrosine Kinases/genetics , Urogenital Abnormalities/genetics , Adolescent , Adult , Animals , Child , Child, Preschool , Databases, Genetic , Disease Models, Animal , Exome/genetics , Female , Haploinsufficiency/genetics , Humans , Intellectual Disability/complications , Kidney/abnormalities , Kidney/embryology , Male , Nephrons/metabolism , Protein Serine-Threonine Kinases/metabolism , Protein-Tyrosine Kinases/metabolism , Urinary Tract/embryology , Urinary Tract/metabolism , Exome Sequencing/methods , Xenopus laevis/genetics , Xenopus laevis/metabolism , Young Adult , Dyrk KinasesABSTRACT
Congenital anomalies of the kidney and urinary tract (CAKUT) occur in â¼1/500 live births and are a leading cause of pediatric kidney failure. With an average wait time of 3-5 years for a kidney transplant, the need is high for the development of new strategies aimed at reducing the incidence of CAKUT and preserving renal function. Next-generation sequencing has uncovered a significant number of putative causal genes, but a simple and efficient model system to examine the function of CAKUT genes is needed. Xenopus laevis (frog) embryos are well-suited to model congenital kidney diseases and to explore the mechanisms that cause these developmental defects. Xenopus has many advantages for studying the kidney: the embryos develop externally and are easily manipulated with microinjections, they have a functional kidney in â¼2â days, and 79% of identified human disease genes have a verified ortholog in Xenopus This facilitates high-throughput screening of candidate CAKUT-causing genes. In this Review, we present the similarities between Xenopus and mammalian kidneys, highlight studies of CAKUT-causing genes in Xenopus and describe how common kidney diseases have been modeled successfully in this model organism. Additionally, we discuss several molecular pathways associated with kidney disease that have been studied in Xenopus and demonstrate why it is a useful model for studying human kidney diseases.
