COL6A3 – Bethlem myopathy

Mutations in COL6A3 underlie Bethlem myopathy, an autosomal dominant collagen VI–related myopathy characterized by proximal muscle weakness and joint contractures. Heterozygous missense variants in the triple-helical and von Willebrand factor A domains have been identified in at least 14 unrelated probands through next-generation and targeted sequencing (PMID:29419890).

Segregation of disease with COL6A3 mutations has been documented in three multi-generation families, including a p.Asp3117Asn variant in a Korean pedigree (PMID:32389683) and a Gly1679Glu substitution co-segregating with Bethlem myopathy in an extended kindred (PMID:10744632). The spectrum of pathogenic alleles is dominated by glycine substitutions within the Gly-X-Y motif; one representative change is c.5036G>A (p.Gly1679Glu), which disrupts local folding and is recurrent across unrelated cases (PMID:10744632).

Functional assays confirm that p.Gly1679Glu impairs the folding of the N2 domain, leading to intracellular retention and degradation of α3(VI) chains and a consequent collagen VI matrix deficiency in patient fibroblasts (PMID:10744632). These data align with the dominant-negative mechanism seen in Bethlem myopathy, whereby mutant chains integrate poorly into the microfibrillar network.

Collectively, the genetic and experimental evidence supports a Strong clinical validity for the COL6A3–Bethlem myopathy association. Diagnostic testing for COL6A3 variants enables precision in molecular diagnosis, informs family counseling on recurrence risk, and underpins emerging targeted therapies such as exon-skipping approaches.

Key take-home: Heterozygous COL6A3 missense mutations cause Bethlem myopathy via a dominant-negative misfolding mechanism, guiding clinical genetic testing and therapeutic development.

References

• FASEB journal • 2000 • A Bethlem myopathy Gly to Glu mutation in the von Willebrand factor A domain N2 of the collagen alpha3(VI) chain interferes with protein folding PMID:10744632
• Clinical genetics • 2018 • Genetic and clinical findings in a Chinese cohort of patients with collagen VI-related myopathies PMID:29419890
• Annals of Indian Academy of Neurology • 2013 • Bethlem myopathy: An autosomal dominant myopathy with flexion contractures, keloids, and follicular hyperkeratosis PMID:24339618
• Clinica chimica acta; international journal of clinical chemistry • 2020 • Coexistence of digenic mutations in the collagen VI genes (COL6A1 and COL6A3) leads to Bethlem myopathy PMID:32389683

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