Association ofMIOXwith Autosomal Dominant Polycystic Kidney Disease

Abstract

AbstractPolycystic Kidney Disease (PKD), which affects 1 in 500 to 1000 people globally, is a monogenic, hereditary nephropathy marked by the gradual growth and expansion of many fluid-filled kidney cysts often resulting in end-stage renal disease. Even within the same family, ADPKD shows variation in phenotype, genotype, and disease severity. WhilePKD1andPKD2mutations account for the majority of ADPKD cases (75% and 15%, respectively), about 7% of cases are currently genetically unexplained. The ADPKD-associated genesGANAB, DNAJB11, andALG9are also found in several genetically unresolved cases. Being a large gene constituted with 46 exons covering a 52 kb area and a 14 kb transcript and with six pseudogenes,PKD1poses a challenge for direct PCR and Sanger sequencing of all exons and exon-intron boundaries for mutation analysis. In order to find the disease-causing mutation(s) in a trio, whole exome sequencing (WES) was carried out. In the affected mother and daughter, no pathogenic variation(s) in thePKD1, PKD2, DNAJB11, GANAB, andALG9candidate genes was observed. However, WES analysis identified a frameshift deletion [c.32del/p.Leu11ArgfsTer61] inMIOXas the most likely cause of the disease shared by both affected individuals. This has not previously been reported in ADPKD. Further, the differential gene expression profile analysis of the data of cysts from GEO database showed reduced expression ofMIOXin cystic samples of ADPKD individuals as compared to minimal cystic tissues (MCT) and control tissue samples. Myo-Inositol Oxygenase, or MIOX, is an enzyme that specifically expresses in renal tubules and catalyses the initial step of the kidney-based myoinositol catabolism pathway. Both affected candidates also shared benign variants and other variations of uncertain significance which might function as modifiers in the development of the disease. Further functional analysis of the variation(s) will clarify whether and howMIOXcontributes to the development of the disease.