Author ORCID Identifier
Date of Graduation
Doctor of Philosophy (PhD)
Congenital anomalies of the kidney and urinary tract (CAKUT) are a leading cause of pediatric kidney failure and encompass a wide range of structural malformations resulting from defects in morphogenesis. CAKUT occur in ∼1/500 live births and 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. Approximately 14% of CAKUT cases have a known genetic component. This low causality suggests that CAKUT is complex and that there are underlying genes and mechanisms which lead to CAKUT that have not been identified. Next-generation sequencing has uncovered a significant number of putative causal genes, including the novel observation that a cohort of patients with DYRK1A haploinsufficiency has a higher prevalence of CAKUT (73% of those assessed), including kidney defects. By using Xenopus laevis as a model we determine that DYRK1A is essential for kidney development. Loss of dyrk1a in Xenopus leads to abnormal kidney formation, which can be rescued. Furthermore, I demonstrate that Dyrk1a perturbations lead to changes in β-catenin during embryogenesis. This dissertation reveals a new gene important for kidney development and disease and also has the potential to impact diagnostic patient treatment strategies for DYRK1A-syndrome patients.
Xenopus laevis, nephron, nephrogenesis, CAKUT, intellectual disability, kidney, exome sequencing