Abstract: FR-PO803
Mechanism of Mutation of AarF Domain-Containing-Kinase 4 (ADCK4) Glomerulopathy
Session Information
- Genetic Diseases of the Kidney - II
November 08, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1002 Genetic Diseases of the Kidneys: Non-Cystic
Author
- Abu-Maziad, Asmaa Soliman, Department of Pediatrics, Tucson, Arizona, United States
Group or Team Name
- Tomiask Lab
Introduction
AarF domain-containing-kinase 4 (ADCK4) is a mitochondrial resident protein kinase belonging to the UbiB protein kinase-like family. ADCK4 is thought to facilitate the ATP dependent biosynthesis of coenzyme Q10 (CoQ10). Mutations in ADCK4 cause early-onset proteinuria, focal segmental glomerulosclerosis/nephrotic syndrome, followed by end-stage renal disease (ESRD). The regulation of ADCK4 in CoQ10 biosynthesis is not well understood
Case Description
We report a patient who was discovered with proteinuria on routine screening at age of five-year-old. Renal biopsy showed FSGS. Renal functions and proteinuria continued to worsen over the years. Whole exome sequence revealed a novel compound heterozygous for two mutations in the aarF domain-containing-kinase 4 (ADCK4) gene. Her father has proteinuria related to fibrillary GN and bilateral duplicated collecting system, brother with right ureteropelvic junction obstruction and sister with unilateral duplicated collecting system. Genetic analysis using whole exome sequencing for this family with proteinuria and structural anomalies of the kidney and urinary tract revealed a novel compound heterozygous mutation in the ADCK4 .
Discussion
We generated a computational model to understand the mechanism of action of 2 novel identified mutations: I346S in the C-lobe of the ADCK4 kinase domain, and a termination at W520 that leads to the truncation of the C-terminal a5 helix. The alterations of ADCK4 c.1560G>A and c.1037T>G are novel mutations. the model suggests potential mechanisms for alterations in protein function through either destabilization of important allosteric interactions necessary for kinase activation and/or conformational changes that facilitate enzyme activity (Figure 1).