Department of Pediatrics, Jichi Medical University, Tochigi, Japan.
Division of Human Genetics, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan.
Mol Genet Genomic Med. 2022 Sep;10(9):e2008. doi: 10.1002/mgg3.2008. Epub 2022 Jun 27.
Actin, alpha, skeletal muscle 1 (ACTA1) is one of the causative genes of nemaline myopathy (NM) and congenital fiber-type disproportion (CFTD). CFTD is characterized by type 1 fiber atrophy and distinguished from NM in the absence of rods. Eight patients with CFTD, including one patient with dilated cardiomyopathy (DCM), have previously been reported. Herein, we report the case of a 10-year-old boy presenting with CFTD and DCM.
We performed exome sequencing and analyzed the effect of Met327Lys mutations on cultured C2C12 muscle cells compared with that seen in the wild type (WT, ACTA1) and previously identified Asp294Val mutations associated with a severe phenotype of CFTD without cardiomyopathy.
Exome sequencing revealed a de novo mutation, c.980 T > A, p.(Met327Lys), in ACTA1 (NM_001100.4). C2C12 cells transfected with the WT plasmid expressed ACTA1 in the nucleus and cytoplasm. Cells with the Asp294Val mutant showed needle-like structures in the cytoplasm, whereas the expression of the Met327Lys mutant resulted in few aggregations but many apoptotic cells.
Apoptosis induced in Met327Lys-transfected muscle cells supports the pathogenicity of the mutation and can be implicated as one of the histopathological features associated with CFTD, as in NM.
α-横纹肌肌动蛋白 1（ACTA1）是肌原纤维病（NM）和先天性纤维类型比例失调（CFTD）的致病基因之一。CFTD 的特征是 1 型纤维萎缩，与不存在杆状的 NM 不同。此前已报道过 8 例 CFTD 患者，包括 1 例扩张型心肌病（DCM）患者。在此，我们报告了一例 10 岁男孩 CFTD 和 DCM 的病例。
我们进行了外显子组测序，并分析了与野生型（WT，ACTA1）和先前鉴定的与无心肌病的 CFTD 严重表型相关的 Asp294Val 突变相比，Met327Lys 突变对培养的 C2C12 肌细胞的影响。
外显子组测序显示 ACTA1 中的一个从头突变 c.980T>A，p.(Met327Lys)（NM_001100.4）。转染 WT 质粒的 C2C12 细胞在核和细胞质中表达 ACTA1。带有 Asp294Val 突变的细胞在细胞质中显示出针状结构，而 Met327Lys 突变的表达导致很少的聚集但许多凋亡细胞。
Met327Lys 转染的肌细胞中诱导的凋亡支持该突变的致病性，并可能与 NM 一样，作为与 CFTD 相关的组织病理学特征之一。
