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.
Highlights
The analysis of the genetic basis of common diseases remains challenging due to their complex pathogenesis and genetic heterogeneity in human populations
In comparison to the reference genome (Rattus norvegicus, ENSEMBL rn6.0) (Yates et al, 2016), we identified 5,158 SNPs and 1893 small insertions and deletions (INDELs) in MWF, and 5326 single nucleotide polymorphisms (SNPs) and 1804 INDELs in SHR (Figure 3—figure supplement 1)
Previous genetic analysis in the fawn-hooded hypertensive (FHH) rat model led to the identification of naturally occurring genetic variants in RAB38, member RAS oncogene family (Rab38), and shroom family member 3 (Shroom3) that successfully complemented studies in humans supporting their role for albuminuria (Rangel-Filho et al, 2013; Yeo et al, 2015)
Summary
The analysis of the genetic basis of common diseases remains challenging due to their complex pathogenesis and genetic heterogeneity in human populations Schulz et al set out to narrow down the list and find specific genes that might contribute to elevated albumin in the urine of rats with high blood pressure This search identified the gene for a protein called TMEM63c as a likely candidate. Following initial QTL mapping in intercrosses of contrasting hypertensive strains (Schulz and Kreutz, 2012), we successfully combined conventional fine mapping using congenic strains with characterization of the genomic architecture in sub-QTLs by targeted next-generation sequencing (NGS), and compartment-specific RNA sequencing (RNA-Seq) analysis This comprehensive approach allowed us to prioritize transmembrane protein Tmem63c as a novel positional target for albuminuria development among several candidates. Ultrastructural analysis by electron microscopy, demonstrated severe morphological defects including podocyte damage with foot process effacement in tmem63c-
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