GWAS in Mice Maps Susceptibility to HIV-Associated Nephropathy to the Ssbp2 Locus

Abstract

BackgroundTo gain insight into the pathogenesis of collapsing glomerulopathy, a rare form of FSGS that often arises in the setting of viral infections, we performed a genome-wide association study (GWAS) among inbred mouse strains using a murine model of HIV-1 associated nephropathy (HIVAN).MethodsWe first generated F1 hybrids between HIV-1 transgenic mice on the FVB/NJ background and 20 inbred laboratory strains. Analysis of histology, BUN, and urinary NGAL demonstrated marked phenotypic variation among the transgenic F1 hybrids, providing strong evidence for host genetic factors in the predisposition to nephropathy. A GWAS in 365 transgenic F1 hybrids generated from these 20 inbred strains was performed.ResultsWe identified a genome-wide significant locus on chromosome 13-C3 and multiple additional suggestive loci. Crossannotation of the Chr. 13 locus, including single-cell transcriptomic analysis of wildtype and HIV-1 transgenic mouse kidneys, nominated Ssbp2 as the most likely candidate gene. Ssbp2 is highly expressed in podocytes, encodes a transcriptional cofactor that interacts with LDB1 and LMX1B, which are both previously implicated in FSGS. Consistent with these data, older Ssbp2 null mice spontaneously develop glomerulosclerosis, tubular casts, interstitial fibrosis, and inflammation, similar to the HIVAN mouse model.ConclusionsThese findings demonstrate the utility of GWAS in mice to uncover host genetic factors for rare kidney traits and suggest Ssbp2 as susceptibility gene for HIVAN, potentially acting via the LDB1-LMX1B transcriptional network.

Collapsing glomerulopathy: unraveling varied pathogeneses

“…These mice develop a collapsing glomerulopathy-like nephropathy, which was later shown to be dependent on the HIV nef and vpr genes [53][54][55][56]. Even though direct infection of renal epithelial cells by HIV remains controversial [57][58][59], the Tg26 model has proven a useful tool for dissecting podocyte injury pathways and for mapping FSGS susceptibility genes in mice [60,61]. In contrast to HIVAN, the clinical and pathologic data of COVID-19-associated collapsing glomerulopathy and subsequent investigations have led to the consensus that direct kidney infection by SARS-CoV-2 is highly unlikely [8,9].…”