Loss-of-function mutations in the co-chaperone protein BAG5 cause dilated cardiomyopathy requiring heart transplantation
Loss-of-function mutations in the co-chaperone protein BAG5 cause dilated cardiomyopathy requiring heart transplantation
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DOI：
10.1126/scitranslmed.abf3274
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发表时间：
2022-01-19
影响因子：
17.1
通讯作者：
Asano, Yoshihiro
中科院分区：
文献类型：
--
作者：
Hakui, Hideyuki;Kioka, Hidetaka;Asano, Yoshihiro
扩张性心肌病（DCM）是心力衰竭的主要原因，其特征是心室扩张和收缩功能障碍。据报道，家族性DCM是由50多个基因突变引起的，需要根据遗传信息进行精确的疾病分层。然而，60%至80%的家族性DCM病例的潜在遗传原因仍然未知。在这里，我们发现，纯合截断突变的基因编码Bcl-2相关的乙醇基因（BAG）共伴侣5（BAG 5）导致遗传性扩张型心肌病在4个不相关的家庭中的5名患者完全无症状。BAG 5作为热休克同源71 kDa蛋白（HSC 70）的核苷酸交换因子，促进腺苷二磷酸释放并激活HSC 70介导的蛋白质折叠。Bag 5突变体基因敲入小鼠在儿茶酚胺刺激下表现出心室扩张、致瘤性和预后不良，重现了人类DCM表型，并且携带野生型BAG 5基因的腺相关病毒9载体的施用可以完全改善这些DCM表型。免疫细胞化学分析显示，BAG 5定位于交界膜复合物（JMC），这是钙处理的关键微结构域。Bag 5突变小鼠心肌细胞表现出减少的功能性JMC蛋白的丰富下，儿茶酚胺刺激，破坏JMC结构，和钙处理异常。我们还在3例心动过速诱导的心肌病患者中发现了杂合性截短突变，这是一种与钙稳态异常相关的可逆性DCM亚型。我们的研究表明，BAG 5中的功能缺失突变可导致DCM，BAG 5可能是DCM病例中基因检测的靶点，基因治疗可能是这种疾病的治疗方法。
Dilated cardiomyopathy (DCM) is a major cause of heart failure, characterized by ventricular dilatation and systolic dysfunction. Familial DCM is reportedly caused by mutations in more than 50 genes, requiring precise disease stratification based on genetic information. However, the underlying genetic causes of 60 to 80% of familial DCM cases remain unknown. Here, we identified that homozygous truncating mutations in the gene encoding Bcl-2-associated athanogene (BAG) co-chaperone 5 (BAG5) caused inherited DCM in five patients among four unrelated families with complete penetrance. BAG5 acts as a nucleotide exchange factor for heat shock cognate 71 kDa protein (HSC70), promoting adenosine diphosphate release and activating HSC70-mediated protein folding. Bag5 mutant knock-in mice exhibited ventricular dilatation, arrhythmogenicity, and poor prognosis under catecholamine stimulation, recapitulating the human DCM phenotype, and administration of an adeno-associated virus 9 vector carrying the wild-type BAG5 gene could fully ameliorate these DCM phenotypes. Immunocytochemical analysis revealed that BAG5 localized to junctional membrane complexes (JMCs), critical microdomains for calcium handling. Bag5-mutant mouse cardiomyocytes exhibited decreased abundance of functional JMC proteins under catecholamine stimulation, disrupted JMC structure, and calcium handling abnormalities. We also identified heterozygous truncating mutations in three patients with tachycardia-induced cardiomyopathy, a reversible DCM subtype associated with abnormal calcium homeostasis. Our study suggests that loss-of-function mutations in BAG5 can cause DCM, that BAG5 may be a target for genetic testing in cases of DCM, and that gene therapy may potentially be a treatment for this disease.