Key result
A novel splicing mutation (c.736-1G>C) in the COL6A2 gene caused aberrant splicing and premature termination of protein translation in three patients with Bethlem myopathy.
Why the study?
The pathogenicity of a novel splice-site mutation remained to be explored in a family with suspected Bethlem myopathy.
Case Report (n=9)
No
RNA-sequencing is a powerful tool for identifying the underlying mechanisms of disease-causing splice-site mutations in Bethlem myopathy.
RNA-sequencing may aid splice mutation analysis in Bethlem myopathy; leaves open routine diagnostic adoption pending validation.
Bethlem myopathy (BM) is an autosomal dominant or autosomal recessive disorder and is usually associated with mutations in the collagen VI genes. In the present study, the pathogenicity of a novel splice‑site mutation was explored using RNA‑sequencing in a family with suspected BM, and a myopathy panel was performed in the proband. The genetic status of all family members was confirmed using Sanger sequencing. Clinical data and magnetic resonance imaging (MRI) features were also documented. In silico analysis was performed to predict the effects of the splice mutation. RNA‑sequencing and reverse transcription (RT)‑PCR were used to assess aberrant splicing. Immunocytochemistry was conducted to measure collagen VI protein levels within the gastrocnemius and in cultured skin fibroblasts. The results revealed that three patients in the family shared a similar classic BM presentation. MRI revealed distinct patterns of fatty infiltration in the lower extremities. A novel splicing mutation c.736‑1G>C in the collagen α‑2 (VI) chain (COL6A2) gene was found in all three patients. In silico analysis predicted that the mutation would destroy the normal splice acceptor site. RNA‑sequencing detected two abnormal splicing variants adjacent to the mutation site, and RT‑PCR confirmed the RNA‑sequencing findings. Furthermore, a defect in the collagen protein within cultured fibroblasts was detected using immunocytochemistry. The mutation c.736‑1G>C in the COL6A2 gene caused aberrant splicing and led to premature termination of protein translation. In conclusion, these findings may improve our knowledge of mutations of the COL6A2 gene associated with BM and demonstrated that RNA‑sequencing can be a powerful tool for finding the underlying mechanism of a disease‑causing mutations at a splice site.
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Zhong et al. (2021) conducted a case report in Bethlem myopathy (n=9). c.736-1G>C mutation in the COL6A2 gene vs. Unaffected family members and healthy controls was evaluated on Pathogenicity and mechanism of the novel splice-site mutation. A novel splicing mutation (c.736-1G>C) in the COL6A2 gene caused aberrant splicing and premature termination of protein translation in three patients with Bethlem myopathy.
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