Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
J Am Soc Nephrol. 2011 Aug;22(8):1497-504. doi: 10.1681/ASN.2011020209. Epub 2011 Jul 22.
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.
HIVAN1、HIVAN2 和 HIVAN3 是先前在 HIV-1 转基因小鼠中鉴定的肾病易感性基因座，该模型为塌陷性肾小球病。HIVAN1 和 HIVAN2 基因座调节编码足细胞蛋白和其他几种足细胞表达基因的 Nphs2 的表达。为了鉴定导致肾病的其他易感基因座，我们在由肾病敏感的 HIV-1 转基因 FVB/NJ (TgFVB) 株和抗性 Balb/cJ (BALB) 株之间产生的 165 只回交小鼠中进行了全基因组扫描。我们在染色体 6 G3-F3 上发现了一个主要的易感基因座（HIVAN4），BALB 等位基因使严重程度降低了两倍（峰值 LOD 评分=4.0）。与 HIVAN1 和 HIVAN2 相似，HIVAN4 调节了 Nphs2 的表达，表明这些基因座具有共同的途径。我们在一个姐妹 TgFVB 群体中独立证实了 HIVAN4 基因座，该群体在经历了繁殖瓶颈后，肾病急剧减轻。在这个低外显率的系中，基因组的 3%与 BALB 等位基因混合，表明存在远程污染事件。混合发生在染色体 2 和 HIVAN4 基因座的离散片段上。HIVAN4 的候选基因包括杀伤性凝集素样受体基因以及 A2m 和 Ptpro，其基因产物在肾小球中富集，并与 HIV-1 蛋白相互作用。总之，这些数据将 HIVAN4 确定为肾病的主要数量性状基因座和 Nphs2 的转录调节剂。此外，类似的选择性繁殖策略可能有助于鉴定其他易感基因座。
