RGD Reference Report - Analysis of the genomic architecture of a complex trait locus in hypertensive rat models links Tmem63c to kidney damage. - Rat Genome Database

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

Authors: Schulz, Angela  Müller, Nicola Victoria  van de Lest, Nina Anne  Eisenreich, Andreas  Schmidbauer, Martina  Barysenka, Andrei  Purfürst, Bettina  Sporbert, Anje  Lorenzen, Theodor  Meyer, Alexander M  Herlan, Laura  Witten, Anika  Rühle, Frank  Zhou, Weibin  de Heer, Emile  Scharpfenecker, Marion  Panáková, Daniela  Stoll, Monika  Kreutz, Reinhold 
Citation: Schulz A, etal., Elife. 2019 Mar 22;8. pii: 42068. doi: 10.7554/eLife.42068.
RGD ID: 15023481
Pubmed: PMID:30900988   (View Abstract at PubMed)
PMCID: PMC6478434   (View Article at PubMed Central)
DOI: DOI:10.7554/eLife.42068   (Journal Full-text)

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.

Disease Annotations    

Gene Ontology Annotations    

Biological Process

Phenotype Annotations    

Mammalian Phenotype
Objects Annotated

Genes (Rattus norvegicus)
Nphs1  (NPHS1 adhesion molecule, nephrin)
Tmem63c  (transmembrane protein 63c)

Genes (Mus musculus)
Nphs1  (nephrosis 1, nephrin)
Tmem63c  (transmembrane protein 63c)

Genes (Homo sapiens)
NPHS1  (NPHS1 adhesion molecule, nephrin)
TMEM63C  (transmembrane protein 63C)

MWF.SHR-(D6Rat1-D6Rat81)/Rkb  (NA)
MWF/FubRkb  (Munich Wistar Fromter)

Objects referenced in this article
Strain MWF.SHR-(D6Rat1-D6Mgh4)/Rkb null Rattus norvegicus
Strain MWF.SHR-(D6Rat1-D6Mit8)/Rkb null Rattus norvegicus
Strain MWF.SHR-(D6Rat1-D6Rat106)/Rkb null Rattus norvegicus
Strain MWF.SHR-(D6Rat1-D6Rat115)/Rkb null Rattus norvegicus
Strain MWF.SHR-(D6Rat1-D6Rat121)/Rkb null Rattus norvegicus
Strain MWF.SHR-(D6Rat1-D6Rat184)/Rkb null Rattus norvegicus
Strain MWF.SHR-(D6Rat1-D6Rat30)/Rkb null Rattus norvegicus

Additional Information