@article{818b43ff86ec4c16b7bd5005041e0c71,
title = "Analysis of the genomic architecture of a complex trait locus in hypertensive rat models links Tmem63c to kidney damage",
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.",
keywords = "WIDE ASSOCIATION, MWF RAT, ALBUMINURIA, PROTEINURIA, PODOCYTES, NEPHRIN, CHANNELS, REPLACEMENT, MUTAGENESIS, EXPRESSION",
author = "Angela Schulz and Mueller, {Nicola Victoria} and {van de Lest}, {Nina Anne} and Andreas Eisenreich and Martina Schmidbauer and Andrei Barysenka and Bettina Purfuerst and Anje Sporbert and Theodor Lorenzen and Meyer, {Alexander M.} and Laura Herlan and Anika Witten and Frank Ruehle and Weibin Zhou and {de Heer}, Emile and Marion Scharpfenecker and Daniela Panakova and Monika Stoll and Reinhold Kreutz",
note = "Funding Information: We acknowledge the contributions of Karen B{\"o}hme, Bettina Bublath, Marianne Jansen-Rust, Claudia Plum, Christiane Priebsch, Christina Schiel, Sabine Wunderlich, and Malu Zandbergen for excellent laboratory or animal assistance. Tg(wt1b:GFP) line was kindly provided by Christoph Englert. This study was supported by the Deutsche Hochdruckliga (DHL) Hypertensiologie Professur to RK, by the grants from the Deutsche Forschungsgemeinschaft (DFG) KR 1152-3-1 (RK) and SCHU 2604/1-1 (ASch), by the DFG (German Research Foundation) - Project number 394046635 - SFB 1365 (RK, DP), and by the grants from the Helmholtz Young Investigator Program VH-NG-736, and Marie Curie CIG from the European Commission (WNT/CALCIUM IN HEART-322189) (DP). Funding Information: We acknowledge the contributions of Karen B{\"o}hme, Bettina Bublath, Marianne Jansen-Rust, Claudia Plum, Christiane Priebsch, Christina Schiel, Sabine Wunderlich†, and Malu Zandbergen for excellent laboratory or animal assistance. Tg(wt1b:GFP) line was kindly provided by Christoph Englert. This study was supported by the Deutsche Hochdruckliga (DHL) Hypertensiologie Professur to RK, by the grants from the Deutsche Forschungsgemeinschaft (DFG) KR 1152-3-1 (RK) and SCHU 2604/1–1 (ASch), by the DFG (German Research Foundation) – Project number 394046635 – SFB 1365 (RK, DP), and by the grants from the Helmholtz Young Investigator Program VH-NG-736, and Marie Curie CIG from the European Commission (WNT/CALCIUM IN HEART-322189) (DP). Publisher Copyright: {\textcopyright} Schulz et al.",
year = "2019",
month = mar,
day = "22",
doi = "10.7554/eLife.42068",
language = "English",
volume = "8",
journal = "Elife",
issn = "2050-084X",
publisher = "eLife Sciences Publications Ltd",
}