Whole exome sequencing identified a novel DAG 1 mutation in a patient with rare, mild and late age of onset muscular dystrophy‐dystroglycanopathy

作者：Yi Dai, Shengran Liang, Xue Dong, Yanhuan Zhao, Haitao Ren, Yuzhou Guan, HaiFang Yin, Chen Li, Lin Chen, Liying Cui, Santasree Banerjee · 发表于：Journal of Cellular and Molecular Medicine · 年份：2018 · DOI：10.1111/jcmm.13979 · 被引用次数：112 · 研究领域：Muscle Physiology and Disorders、Ubiquitin and proteasome pathways、Genetic Neurodegenerative Diseases

Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 9 (MDDGC9) is the rarest type of autosomal recessive muscular dystrophies. MDDGC9 is manifested with an early onset in childhood. Patients with MDDGC9 usually identified with defective glycosylation of DAG1, hence it is known as "dystroglycanopathies". Here, we report a Chinese pedigree presented with mild MDDGC9. The proband is a 64 years old Chinese man. In this family, both the proband and proband's younger brother have been suffering from mild and late onset MDDGC9. Muscle biopsy showed that the left deltoid muscle with an advanced stage of dystrophic change. Immunohistochemistry staining of dystrophin, α-sarcoglycan, β-sarcoglycan and dysferlin are normal. Molecular genetic analysis of the proband has been done with whole exome sequencing. A homozygous novel missense mutation (c.2326C>T; p.R776C) in the exon 3 of the DAG1 gene has been identified in the proband. Sanger sequencing revealed that this missense mutation is co-segregated well among the affected and unaffected (carrier) family members. This mutation is not detected in 200 normal healthy control individuals. This novel homozygous missense mutation (c.2326C>T) causes substitution of arginine by cystine at the position of 776 (p.R776C) which is evolutionarily highly conserved. Immunoblotting studies revealed that a significant reduction of α-dystroglycan expression in the muscle tissue. The novelty of our study is that it is a first report of DAG1 assoc...