Mutations in INF2 Are a Major Cause of Autosomal Dominant Focal Segmental Glomerulosclerosis
Mutations in INF2 Are a Major Cause of Autosomal Dominant Focal Segmental Glomerulosclerosis
复制标题
DOI：
10.1681/asn.2010050518
复制
发表时间：
2011-02-01
影响因子：
13.6
通讯作者：
Antignac, Corinne
中科院分区：
文献类型：
--
作者：
Boyer, Olivia;Benoit, Genevieve;Antignac, Corinne
在家族性FSGS的情况下，最近鉴定出编码肌动蛋白调节蛋白家族成员的INF 2基因突变，支持完整肌动蛋白细胞骨架在足细胞功能中的重要性。为了更好地确定常染色体显性FSGS中INF 2突变的患病率，我们筛选了54个家族（78例患者），并在其中17%的患者中检测到突变。所有突变均为位于蛋白质N-末端透明抑制结构域的错义变体，该区域与C-末端透明自动调节结构域相互作用，从而竞争肌动蛋白单体结合并抑制解聚。七个不同的改变的残基中有六个位于INF 2区域，该区域对应于mDia 1透明抑制结构域的一个亚结构域，该亚结构域与含有GTP酶激活蛋白1（IQGAP 1）的IQ基序共免疫沉淀。此外，我们评估了84例散发病例，但仅在1例患者中检测到突变。总之，INF 2突变是常染色体显性FSGS的主要原因。由于IQGAP 1与关键的足细胞蛋白（如nephrin和PLC β 1）相互作用，因此可能改变推定的INF 2 IQGAP 1相互作用的突变的鉴定提供了对将α蛋白与足细胞功能障碍和FSGS联系起来的病理生理机制的额外见解。
The recent identification of mutations in the INF2 gene, which encodes a member of the formin family of actin-regulating proteins, in cases of familial FSGS supports the importance of an intact actin cytoskeleton in podocyte function. To determine better the prevalence of INF2 mutations in autosomal dominant FSGS, we screened 54 families (78 patients) and detected mutations in 17% of them. All mutations were missense variants localized to the N-terminal diaphanous inhibitory domain of the protein, a region that interacts with the C-terminal diaphanous autoregulatory domain, thereby competing for actin monomer binding and inhibiting depolymerization. Six of the seven distinct altered residues localized to an INF2 region that corresponded to a subdomain of the mDia1 diaphanous inhibitory domain reported to co-immunoprecipitate with IQ motif containing GTPase-activating protein 1 (IQGAP1). In addition, we evaluated 84 sporadic cases but detected a mutation in only one patient. In conclusion, mutations in INF2 are a major cause of autosomal dominant FSGS. Because IQGAP1 interacts with crucial podocyte proteins such as nephrin and PLC epsilon 1, the identification of mutations that may alter the putative INF2 IQGAP1 interaction provides additional insight into the pathophysiologic mechanisms linking formin proteins to podocyte dysfunction and FSGS.