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

Mar 22, 2019

https://doi.org/10.7554/eLife.42068

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Abstract
Data availability
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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).

The following data sets were generated

1. Barysenka A
2. Schulz A
3. van de Lest NA
4. Eisenreich A
5. Schmidbauer M
6. Müller N
7. Lorenzen T
8. Meyer A
9. Herlan L
10. Witten A
11. Rühle F
12. Zhou W
13. de Heer E
14. Scharpfenecker M
15. Panakova D
16. Stoll M
17. Kreutz R
(2017) Integrative analysis of the genomic architecture of a complex kidney damage QTL in inbred hypertensive rats implies Tmem63c for translational research
NCBI BioProject, PRJNA398197.

https://www.ncbi.nlm.nih.gov/bioproject/?term=PRJNA398197
1. Barysenka A
2. Schulz A
3. van de Lest NA
4. Eisenreich A
5. Schmidbauer M
6. Müller N
7. Lorenzen T
8. Meyer A
9. Herlan L
10. Witten A
11. Rühle F
12. Zhou W
13. de Heer E
14. Scharpfenecker M
15. Panakova D
16. Stoll M
17. Kreutz R
(2017) Integrative analysis of the genomic architecture of a complex kidney damage QTL in inbred hypertensive rats implies Tmem63c for translational research
NCBI Gene Expression Omnibus, GSE102546.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE102546

Article and author information

Author details

Angela Schulz

Institute of Clinical Pharmacology and Toxicology, Charité - Universitätsmedizin Berlin, Berlin, Germany

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-4576-8035
Nicola Victoria Müller

Institute of Clinical Pharmacology and Toxicology, Charité - Universitätsmedizin Berlin, Berlin, Germany

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-7261-830X
Nina Anne van de Lest

Department of Pathology, Leiden University Medical Center, Leiden, Netherlands

Competing interests
The authors declare that no competing interests exist.
Andreas Eisenreich

Institute of Clinical Pharmacology and Toxicology, Charité - Universitätsmedizin Berlin, Berlin, Germany

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The authors declare that no competing interests exist.
Martina Schmidbauer

Institute of Clinical Pharmacology and Toxicology, Charité - Universitätsmedizin Berlin, Berlin, Germany

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The authors declare that no competing interests exist.
Andrei Barysenka

Genetic Epidemiology, Institute for Human Genetics, Westfälische Wilhelms University, Münster, Germany

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The authors declare that no competing interests exist.
Bettina Purfürst

Core Facility Electron Microscopy, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany

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The authors declare that no competing interests exist.
Anje Sporbert

Advanced Light Microscopy, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany

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The authors declare that no competing interests exist.
Theodor Lorenzen

Institute of Clinical Pharmacology and Toxicology, Charité - Universitätsmedizin Berlin, Berlin, Germany

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The authors declare that no competing interests exist.
Alexander M Meyer

Electrochemical Signaling in Development and Disease, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany

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The authors declare that no competing interests exist.
Laura Herlan

Institute of Clinical Pharmacology and Toxicology, Charité - Universitätsmedizin Berlin, Berlin, Germany

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The authors declare that no competing interests exist.
Anika Witten

Genetic Epidemiology, Institute for Human Genetics, Westfälische Wilhelms University, Münster, Germany

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The authors declare that no competing interests exist.
Frank Rühle

Genetic Epidemiology, Institute for Human Genetics, Westfälische Wilhelms University, Münster, Germany

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The authors declare that no competing interests exist.
Weibin Zhou

Center for Human Disease Modeling, Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, United States

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The authors declare that no competing interests exist.
Emile de Heer

Department of Pathology, Leiden University Medical Center, Leiden, Netherlands

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The authors declare that no competing interests exist.
Marion Scharpfenecker

Department of Pathology, Leiden University Medical Center, Leiden, Netherlands

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The authors declare that no competing interests exist.
Daniela Panáková

Electrochemical Signaling in Development and Disease, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany

For correspondence
daniela.panakova@mdc-berlin.de

Competing interests
The authors declare that no competing interests exist.
Monika Stoll

Department of Genetic Epidemiology, Westfälische Wilhelms University, Münster, Germany

Competing interests
The authors declare that no competing interests exist.
Reinhold Kreutz

Institute of Clinical Pharmacology and Toxicology, Charité - Universitätsmedizin Berlin, Berlin, Germany

For correspondence
reinhold.kreutz@charite.de

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-4818-211X

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

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.