Somatic Mutations in Renal Cyst Epithelium in Autosomal Dominant Polycystic Kidney Disease. Academic Article uri icon

Overview

abstract

  • BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is a ciliopathy caused by mutations in PKD1 and PKD2 that is characterized by renal tubular epithelial cell proliferation and progressive CKD. Although the molecular mechanisms involved in cystogenesis are not established, concurrent inactivating constitutional and somatic mutations in ADPKD genes in cyst epithelium have been proposed as a cellular recessive mechanism. METHODS: We characterized, by whole-exome sequencing (WES) and long-range PCR techniques, the somatic mutations in PKD1 and PKD2 genes in renal epithelial cells from 83 kidney cysts obtained from nine patients with ADPKD, for whom a constitutional mutation in PKD1 or PKD2 was identified. RESULTS: Complete sequencing data by long-range PCR and WES was available for 63 and 65 cysts, respectively. Private somatic mutations of PKD1 or PKD2 were identified in all patients and in 90% of the cysts analyzed; 90% of these mutations were truncating, splice site, or in-frame variations predicted to be pathogenic mutations. No trans-heterozygous mutations of PKD1 or PKD2 genes were identified. Copy number changes of PKD1 ranging from 151 bp to 28 kb were observed in 12% of the cysts. WES also identified significant mutations in 53 non-PKD1/2 genes, including other ciliopathy genes and cancer-related genes. CONCLUSIONS: These findings support a cellular recessive mechanism for cyst formation in ADPKD caused primarily by inactivating constitutional and somatic mutations of PKD1 or PKD2 in kidney cyst epithelium. The potential interactions of these genes with other ciliopathy- and cancer-related genes to influence ADPKD severity merits further evaluation.

publication date

  • July 24, 2018

Research

keywords

  • Epithelial Cells
  • Kidney Transplantation
  • Polycystic Kidney, Autosomal Dominant
  • TRPP Cation Channels

Identity

PubMed Central ID

  • PMC6065086

Scopus Document Identifier

  • 85050943371

Digital Object Identifier (DOI)

  • 10.1681/ASN.2017080878

PubMed ID

  • 30042192

Additional Document Info

volume

  • 29

issue

  • 8