An Intronic Heterozygous SYNE2 Splice Site Mutation: A Rare Cause for Myalgia and hyperCKemia?

Area of Science:

• Genetics and Molecular Biology
• Neuromuscular Disorders

Background:

• Mutations in the SYNE2 gene are linked to muscle diseases like Emery-Dreifuss muscular dystrophy (EDMD).
• EDMD affects skeletal and cardiac muscles, leading to progressive muscle weakness and contractures.

Observation:

• A 70-year-old male presented with muscle pain and elevated serum creatine kinase (hyperCKemia).
• Whole-exome sequencing identified a novel heterozygous SYNE2 splice site mutation (c.15306+2T>G).
• Patient-derived cells showed nuclear shape abnormalities and reduced nesprin-2 giant protein at the nuclear envelope.

Findings:

• The SYNE2 mutation likely disrupts the donor splice site in intron 82, causing a splicing defect.
• Immunofluorescence revealed altered nuclear morphology in patient's skeletal muscle and dermal cells.
• Reduced localization of nesprin-2 giant protein was observed in patient fibroblasts.

Implications:

• This novel SYNE2 mutation represents a rare cause of myalgia and hyperCKemia.
• The findings highlight the role of SYNE2 in maintaining nuclear envelope integrity and muscle function.
• Understanding this splicing defect could inform future diagnostic and therapeutic strategies for related myopathies.