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

doi:10.7554/eLife.42068

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 journal › Article › Academic › peer-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 language	English
Article number	42068
Number of pages	33
Journal	Elife
Volume	8
DOIs	https://doi.org/10.7554/eLife.42068
Publication status	Published - 22 Mar 2019

Keywords

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

Access to Document

10.7554/eLife.42068

Cite this

Schulz, A., Mueller, N. V., van de Lest, N. A., Eisenreich, A., Schmidbauer, M., Barysenka, A., Purfuerst, B., Sporbert, A., Lorenzen, T., Meyer, A. M., Herlan, L., Witten, A., Ruehle, F., Zhou, W., de Heer, E., Scharpfenecker, M., Panakova, D., Stoll, M., & Kreutz, R. (2019). Analysis of the genomic architecture of a complex trait locus in hypertensive rat models links Tmem63c to kidney damage. Elife, 8, [42068]. https://doi.org/10.7554/eLife.42068

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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",

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Schulz, A, Mueller, NV, van de Lest, NA, Eisenreich, A, Schmidbauer, M, Barysenka, A, Purfuerst, B, Sporbert, A, Lorenzen, T, Meyer, AM, Herlan, L, Witten, A, Ruehle, F, Zhou, W, de Heer, E, Scharpfenecker, M, Panakova, D, Stoll, M & Kreutz, R 2019, 'Analysis of the genomic architecture of a complex trait locus in hypertensive rat models links Tmem63c to kidney damage', Elife, vol. 8, 42068. https://doi.org/10.7554/eLife.42068

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AU - Schulz, Angela

AU - Mueller, Nicola Victoria

AU - van de Lest, Nina Anne

AU - Eisenreich, Andreas

AU - Schmidbauer, Martina

AU - Barysenka, Andrei

AU - Purfuerst, Bettina

AU - Sporbert, Anje

AU - Lorenzen, Theodor

AU - Meyer, Alexander M.

AU - Herlan, Laura

AU - Witten, Anika

AU - Ruehle, Frank

AU - Zhou, Weibin

AU - de Heer, Emile

AU - Scharpfenecker, Marion

AU - Panakova, Daniela

AU - Stoll, Monika

AU - Kreutz, Reinhold

PY - 2019/3/22

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N2 - 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.

AB - 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.

KW - WIDE ASSOCIATION

KW - MWF RAT

KW - ALBUMINURIA

KW - PROTEINURIA

KW - PODOCYTES

KW - NEPHRIN

KW - CHANNELS

KW - REPLACEMENT

KW - MUTAGENESIS

KW - EXPRESSION

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