Analysis of the genomic architecture of a complex trait locus in hypertensive rat models links Tmem63c to kidney damage

Angela Schulz, Nicola Victoria Mueller, Nina Anne van de Lest, Andreas Eisenreich, Martina Schmidbauer, Andrei Barysenka, Bettina Purfuerst, Anje Sporbert, Theodor Lorenzen, Alexander M. Meyer, Laura Herlan, Anika Witten, Frank Ruehle, Weibin Zhou, Emile de Heer, Marion Scharpfenecker, Daniela Panakova*, Monika Stoll, Reinhold Kreutz*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

13 Citations (Web of Science)

Abstract

Unraveling the genetic susceptibility of complex diseases such as chronic kidney disease remains challenging. Here, we used inbred rat models of kidney damage associated with elevated blood pressure for the comprehensive analysis of a major albuminuria susceptibility locus detected in these models. We characterized its genomic architecture by congenic substitution mapping, targeted next-generation sequencing, and compartment-specific RNA sequencing analysis in isolated glomeruli. This led to prioritization of transmembrane protein Tmem63c as a novel potential target. Tmem63c is differentially expressed in glomeruli of allele-specific rat models during onset of albuminuria. Patients with focal segmental glomerulosclerosis exhibited specific TMEM63C loss in podocytes. Functional analysis in zebrafish revealed a role for tmem63c in mediating the glomerular filtration barrier function. Our data demonstrate that integrative analysis of the genomic architecture of a complex trait locus is a powerful tool for identification of new targets such as Tmem63c for further translational investigation.

Original languageEnglish
Article number42068
Number of pages33
JournalElife
Volume8
DOIs
Publication statusPublished - 22 Mar 2019

Keywords

  • WIDE ASSOCIATION
  • MWF RAT
  • ALBUMINURIA
  • PROTEINURIA
  • PODOCYTES
  • NEPHRIN
  • CHANNELS
  • REPLACEMENT
  • MUTAGENESIS
  • EXPRESSION

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