Novel TUBA4A variant causes congenital myopathy with focal myofibrillar disorganisation

作者：Yalan Wan, Chao Zhou, Xingzhi Chang, Liwen Wu, Yilei Zheng, Jiaxi Yu, Bai Li, Mingyue Luan, Meng Yu, Qi Wang, Wei Zhang, Yun Yuan, Jianwen Deng, Zhaoxia Wang · 发表于：Journal of Medical Genetics · 年份：2024 · DOI：10.1136/jmg-2023-109786 · 被引用次数：10 · 研究领域：Nuclear Structure and Function、Cardiomyopathy and Myosin Studies、Skin and Cellular Biology Research

Background Congenital myopathies are a clinical, histopathological and genetic heterogeneous group of inherited muscle disorders that are defined on peculiar architectural abnormalities in the muscle fibres. Although there have been at least 33 different genetic causes of the disease, a significant percentage of congenital myopathies remain genetically unresolved. The present study aimed to report a novel TUBA4A variant in two unrelated Chinese patients with sporadic congenital myopathy. Methods A comprehensive strategy combining laser capture microdissection, proteomics and whole-exome sequencing was performed to identify the candidate genes. In addition, the available clinical data, myopathological changes, the findings of electrophysiological examinations and thigh muscle MRIs were also reviewed. A cellular model was established to assess the pathogenicity of the TUBA4A variant. Results We identified a recurrent novel heterozygous de novo c.679C>T (p.L227F) variant in the TUBA4A (NM_006000), encoding tubulin alpha-4A, in two unrelated patients with clinicopathologically diagnosed sporadic congenital myopathy. The prominent myopathological changes in both patients were muscle fibres with focal myofibrillar disorganisation and rimmed vacuoles. Immunofluorescence showed ubiquitin-positive TUBA4A protein aggregates in the muscle fibres with rimmed vacuoles. Overexpression of the L227F mutant TUBA4A resulted in cytoplasmic aggregates which colocalised with ubiquitin in cellu...