Mutations in FN1 cause glomerulopathy with fibronectin deposits
Mutations in FN1 cause glomerulopathy with fibronectin deposits
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DOI：
10.1073/pnas.0707730105
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发表时间：
2008-02-19
影响因子：
11.1
通讯作者：
Noris, Marina
中科院分区：
文献类型：
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作者：
Castelletti, Federica;Donadelli, Roberta;Noris, Marina
纤连蛋白 (FN) 沉积肾小球病 (GFND) 是一种常染色体显性遗传疾病，外显率与年龄相关，其特征为蛋白尿、镜下血尿、高血压和肾小球内大量 FN 沉积，导致终末期肾功能衰竭。 GFND 背后的遗传异常尚不清楚。我们假设编码 FN 的 FN1 突变是 GFND 的原因。在一个有 8 名受影响受试者的大型意大利谱系中，我们发现 2q32 的 FN1 基因座与 GFND 存在连锁。我们对 15 个不相关的家系中的 FN1 进行了测序，发现了三种杂合错义突变，即 W1925R、L1974R 和 Y973C，它们与 6 个家系中的疾病共分离。这些突变影响 FN 的两个结构域（W1925R 和 L1974R 的 Hep-II 结构域，以及 Y973C 的 Hep-III 结构域），它们在 FN 细胞相互作用和 FN 纤维形成中发挥关键作用。表达突变重组 Hep-II 片段，功能研究显示与野生型 Hep-II 相比，与肝素、内皮细胞和足细胞的结合较低，并且诱导内皮细胞扩散和细胞骨架重组的能力受损。在我们的研究组中，FN1 总体显性突变占 GFND 病例的 40%。这些发现可能有助于了解 GFND 以及糖尿病肾病、IgA 肾病和狼疮性肾炎等更常见肾脏疾病中蛋白尿和肾小球 FIN 沉积的发病机制。据我们所知，之前没有报道过 FN1 突变会导致人类疾病。
Glomerulopathy with fibronectin (FN) deposits (GFND) is an autosomal dominant disease with age-related penetrance, characterized by proteinuria, microscopic hematuria, hypertension, and massive glomerular deposits of FN that lead to end-stage renal failure. The genetic abnormality underlying GFND was still unknown. We hypothesized that mutations in FN1, which encodes FN, were the cause of GFND. In a large Italian pedigree with eight affected subjects, we found linkage with GFND at the FN1 locus at 2q32. We sequenced the FN1 in 15 unrelated pedigrees and found three heterozygous missense mutations, the W1925R, L1974R, and Y973C, that cosegregated with the disease in six pedigrees. The mutations affected two domains of FN (Hep-II domain for the W1925R and the L1974R, and Hep-III domain for the Y973C) that play key roles in FN-cell interaction and in FN fibrillogenesis. Mutant recombinant Hep-II fragments were expressed, and functional studies revealed a lower binding to heparin and to endothelial cells and podocytes compared with wild-type Hep-II and an impaired capability to induce enclothelial cell spreading and cytoskeletal reorganization. Overall dominant mutations in FN1 accounted for 40% of cases of GFND in our study group. These findings may help understanding the pathogenesis of proteinuria and glomerular FIN deposits in GFND and possibly in more common renal diseases such as diabetic nephropathy, IgA nephropathy, and lupus nephritis. To our knowledge no FN1 mutation causing a human disease was previously reported.