title: Identification of the nephropathy-susceptibility locus HIVAN4.
abstract: HIVAN1, HIVAN2, and HIVAN3 are nephropathy-susceptibility loci previously identified in the HIV-1 transgenic mouse, a model of collapsing glomerulopathy. The HIVAN1 and HIVAN2 loci modulate expression of Nphs2, which encodes podocin and several other podocyte-expressed genes. To identify additional loci predisposing to nephropathy, we performed a genome-wide scan in 165 backcross mice generated between the nephropathy-sensitive HIV-1-transgenic FVB/NJ (TgFVB) strain and the resistant Balb/cJ (BALB) strain. We identified a major susceptibility locus (HIVAN4) on chromosome 6 G3-F3, with BALB alleles conferring a twofold reduction in severity (peak LOD score = 4.0). Similar to HIVAN1 and HIVAN2, HIVAN4 modulated expression of Nphs2, indicating a common pathway underlying these loci. We independently confirmed the HIVAN4 locus in a sister TgFVB colony that experienced a dramatic loss of nephropathy subsequent to a breeding bottleneck. In this low-penetrance line, 3% of the genome was admixed with BALB alleles, suggesting a remote contamination event. The admixture localized to discrete segments on chromosome 2 and at the HIVAN4 locus. HIVAN4 candidate genes include killer lectin-like receptor genes as well as A2m and Ptpro, whose gene products are enriched in the glomerulus and interact with HIV-1 proteins. In summary, these data identify HIVAN4 as a major quantitative trait locus for nephropathy and a transregulator of Nphs2. Furthermore, similar selective breeding strategies may help identify further susceptibility loci.
authors.affiliation: Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
authors.forename: Sindhuri
authors.initials: S
authors.lastname: Prakash
authors.forename: Natalia
authors.initials: N
authors.lastname: Papeta
authors.forename: Roel
authors.initials: R
authors.lastname: Sterken
authors.forename: Zongyu
authors.initials: Z
authors.lastname: Zheng
authors.forename: Robert L
authors.initials: RL
authors.lastname: Thomas
authors.forename: Zhenzhen
authors.initials: Z
authors.lastname: Wu
authors.forename: John R
authors.initials: JR
authors.lastname: Sedor
authors.forename: Vivette D
authors.initials: VD
authors.lastname: D'Agati
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Bruggeman
authors.forename: Ali G
authors.initials: AG
authors.lastname: Gharavi
mesh_terms: D000483:Alleles; D000818:Animals; D002874:Chromosome Mapping; D003433:Crosses, Genetic; D005260:Female; D020022:Genetic Predisposition to Disease; D015497:HIV-1 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007674:Kidney Diseases / Q000175:diagnosis / Q000235:genetics*; D008126:Lod Score; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D008957:Models, Genetic
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C407223:NPHS2 protein