FBXO32, encoding a member of the SCF complex, is mutated in dilated cardiomyopathy.
FBXO32, encoding a member of the SCF complex, is mutated in dilated cardiomyopathy.
复制标题
DOI：
10.1186/s13059-015-0861-4
复制
发表时间：
2016-01-11
期刊：
影响因子：
12.3
通讯作者：
Poizat C
中科院分区：
文献类型：
--
作者：
Al-Yacoub N;Shaheen R;Awad SM;Kunhi M;Dzimiri N;Nguyen HC;Xiong Y;Al-Buraiki J;Al-Habeeb W;Alkuraya FS;Poizat C
扩张型心肌病(DCM)是一种常见的心肌病，可导致收缩功能障碍和心力衰竭。到目前为止，已有30多个基因的罕见变异与家族性扩张性心肌病有关，这些基因大多编码肌瘤蛋白和细胞骨架蛋白。然而，引起扩张性心肌病的大多数变异仍有待鉴定。这项研究的目的是确定导致家族性扩张型心肌病的新突变。我们发现F-Box蛋白家族成员FBXO32(ATROGIN 1)是一个新的DCM致病基因。错义突变会影响一种高度保守的氨基酸，并被预测会严重损害与SCF蛋白的结合。来自表达突变蛋白的细胞和来自两名受影响患者的人类心脏组织的免疫共沉淀实验证实了这一点。我们还证明，FBXO32突变患者的心脏显示出调节自噬的特定蛋白的积累。我们的结果表明，由于一个新的FBXO32突变导致的SCF活性异常以及随后的自噬通量受损，可能与DCM的发病有关。本文的在线版本(doi：10.1186/s13059-0150861-4)包含补充材料，授权用户可以使用。
Dilated cardiomyopathy (DCM) is a common form of cardiomyopathy causing systolic dysfunction and heart failure. Rare variants in more than 30 genes, mostly encoding sarcomeric proteins and proteins of the cytoskeleton, have been implicated in familial DCM to date. Yet, the majority of variants causing DCM remain to be identified. The goal of the study is to identify novel mutations causing familial dilated cardiomyopathy. We identify FBXO32 (ATROGIN 1), a member of the F-Box protein family, as a novel DCM-causing locus. The missense mutation affects a highly conserved amino acid and is predicted to severely impair binding to SCF proteins. This is validated by co-immunoprecipitation experiments from cells expressing the mutant protein and from human heart tissue from two of the affected patients. We also demonstrate that the hearts of the patients with the FBXO32 mutation show accumulation of selected proteins regulating autophagy. Our results indicate that abnormal SCF activity with subsequent impairment of the autophagic flux due to a novel FBXO32 mutation is implicated in the pathogenesis of DCM. The online version of this article (doi:10.1186/s13059-015-0861-4) contains supplementary material, which is available to authorized users.