Table_1_Truncating Variant in Myof Gene Is Associated With Limb-Girdle Type Muscular Dystrophy and Cardiomyopathy.docx

Even though genetic studies of individuals with neuromuscular diseases have uncovered the molecular background of many cardiac disorders such as cardiomyopathies and inherited arrhythmic syndromes, the genetic cause of a proportion of cardiomyopathies associated with neuromuscular phenotype still remains unknown. Here, we present an individual with a combination of cardiomyopathy and limb-girdle type muscular dystrophy where whole exome sequencing identified myoferlin (MYOF)—a member of the Ferlin protein family and close homolog of DYSF—as the most likely candidate gene. The disease-causative role of the identified variant c.[2576delG; 2575G>C], p.G859QfsTer8 is supported by functional studies in vitro using the primary patient’s skeletal muscle mesenchymal progenitor cells, including both RNA sequencing and morphological studies, as well as recapitulating the muscle phenotype in vivo in zebrafish. We provide the first evidence supporting a role of MYOF in human muscle disease.

尽管针对神经肌肉疾病患者的遗传学研究已阐明了包括心肌病、遗传性心律失常综合征在内的多种心脏疾病的分子致病机制，但仍有部分伴随神经肌肉表型的心肌病，其遗传病因尚未明确。本研究报道1例同时合并心肌病与肢带型肌营养不良症的患者，通过全外显子组测序鉴定出肌铁蛋白（MYOF）——Ferlin蛋白家族成员、与DYSF高度同源的蛋白——为最有可能的候选致病基因。经鉴定的变异位点c.[2576delG; 2575G>C]、p.G859QfsTer8的致病作用，通过使用患者原代骨骼肌间充质祖细胞的体外功能实验得到验证：实验涵盖RNA测序与形态学研究，同时在斑马鱼体内成功重现了肌肉病变表型。本研究首次提供证据，证实MYOF在人类肌肉疾病中发挥致病作用。