Analysis of the genomic architecture of a complex trait locus in hypertensive rat models links Tmem63c to kidney damage
- Charité - Universitätsmedizin Berlin, Germany
- Leiden University Medical Center, Netherlands
- Westfälische Wilhelms University, Germany
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Germany
- Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Germany
- Duke University School of Medicine, United States
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.
Data availability
The genomic and transcriptomic data from this publication have been deposited to the NCBI curated repositories, GEO, and SRA, and assigned the identifier SubmissionID: SUB2950675 and BioProject ID: PRJNA398197 (DNA-Seq) and accession GSE102546 (RNA-Seq).
Article and author information
Author details
Nicola Victoria Müller
Funding
Deutsche Hochdruckliga
- Reinhold Kreutz
Deutsche Forschungsgemeinschaft (DFG KR 1152-3-1)
- Reinhold Kreutz
Helmholtz-Gemeinschaft (VH-NG-736)
- Daniela Panáková
European Commission (WNT/CALCIUM IN HEART-322189)
- Daniela Panáková
Deutsche Forschungsgemeinschaft (SCHU 2604/1-1)
- Angela Schulz
Deutsche Forschungsgemeinschaft (Project number 394046635 - SFB 1365)
- Reinhold Kreutz
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All experimental work in rat models was performed in accordance with the guidelines of the Charité-Universitätsmedizin Berlin and the local authority for animal protection (Landesamt für Gesundheit und Soziales, Berlin, Germany) for the use of laboratory animals. The registration numbers for the rat experiments are G 0255/09 and T 0189/02. Zebrafish were bred, raised and maintained in accordance with the guidelines of the Max Delbrück Center for Molecular Medicine and the local authority for animal protection (Landesamt für Gesundheit und Soziales, Berlin, Germany) for the use of laboratory animals, and followed the 'Principles of Laboratory Animal Care' (NIH publication no. 86-23, revised 1985) as well as the current version of German Law on the Protection of Animals.
Human subjects: All biopsy samples were handled and analyzed anonymously in accordance with the Dutch National Ethics Guidelines (Code for Proper Secondary Use of Human Tissue, Dutch Federation of Medical Scientific Societies). Because this study concerned retrospectively collected anonymized material, no informed consent was necessary following the Dutch National Ethics Guidelines. This study is in agreement with the Declaration of Helsinki and the Department of Health and Human Services Belmont Report and the use of the patient biopsies was approved by the medical ethical committee of the LUMC (registration number G16.110).
Copyright
© 2019, Schulz et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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