Author ORCID Identifier

https://orcid.org/0000-0003-2974-0339

Date of Graduation

5-2021

Document Type

Dissertation (PhD)

Program Affiliation

Biomedical Sciences

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Rachel Miller

Committee Member

Rebecca Berdeaux

Committee Member

Vicki Huff

Committee Member

Pierre McCrea

Committee Member

George Eisenhoffer

Committee Member

Reza Bekheirnia

Abstract

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.

Keywords

Xenopus laevis, nephron, nephrogenesis, CAKUT, intellectual disability, kidney, exome sequencing

Available for download on Thursday, January 06, 2022

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