Association of MIOX with Autosomal Dominant Polycystic Kidney Disease

Polycystic 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. While PKD1 and PKD2 mutations account for the majority of ADPKD cases (75% and 15%, respectively), about 7% of cases are currently genetically unexplained. The ADPKD-associated genes GANAB, DNAJB11, and ALG9 are 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, PKD1 poses 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 the PKD1, PKD2, DNAJB11, GANAB, and ALG9 candidate genes was observed. However, WES analysis identified a frameshift deletion [c.32del/p.Leu11ArgfsTer61] in MIOX as 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 of MIOX in 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 how MIOX contributes to the development of the disease. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by the Department of Biotechnology (DBT) and the Indian Council of Medical Research (ICMR), India. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The institutional Ethics committee of the Institute of Science, Banaras Hindu University gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors