COL6A1 – Bethlem Myopathy

Bethlem myopathy is a slowly progressive collagen VI–related myopathy characterized by early-onset proximal muscle weakness, distal joint hyperextensibility, and multiple flexion contractures. The disorder most often follows an autosomal dominant inheritance pattern and is caused by heterozygous mutations in COL6A1, COL6A2, or COL6A3, with COL6A1 accounting for a substantial proportion of cases (PMID:11932968).

Genetic studies have identified both private and recurrent COL6A1 variants in multiple unrelated families. A c.428+1G>A splice‐site mutation segregated with disease in a four‐generation Italian pedigree, leading to in‐frame deletion of 22 amino acids and absence of the mutant chain (PMID:11932968). In a cohort of 16 Bethlem patients, four splicing and four missense COL6A1 mutations were detected, confirming dominant inheritance and segregation in at least 16 families (PMID:15955946). Case series describe additional dominant splice‐site (e.g., c.1056+1G>A) and missense (e.g., c.877G>C (p.Gly293Arg)) mutations with co‐segregation in affected relatives (PMID:12401455).

The COL6A1 variant spectrum encompasses canonical splice‐site mutations, glycine substitutions in the triple‐helix domain, in‐frame deletions, and deep intronic pseudoexon‐inducing changes. Recurrent deep intronic c.930+189C>T has been shown to activate a cryptic splice donor, inserting a pseudoexon and causing a dominant‐negative effect (PMID:38585825). Glycine substitutions cluster in the Gly-X-Y repeats, particularly N‐terminal to the 17th triplet, correlating with phenotype severity (PMID:24038877).

Functional analyses demonstrate that mutant COL6A1 transcripts are stable but produce unstable protein chains that are degraded or secreted as abnormal monomers. Fibroblasts from mutation carriers show reduced collagen VI synthesis and extracellular deposition by Western blot and immunofluorescence (PMID:11932968; PMID:17886299). Patient‐specific iPSC models and CRISPR/Cas9‐edited fibroblasts confirm rescue of collagen VI networks upon allele correction or exon skipping.

Pathogenicity is primarily mediated by dominant‐negative disruption of collagen VI microfibril assembly, although haploinsufficiency from unstable chains also contributes. Some reports of compound heterozygous COL6A1 alleles suggest rare autosomal recessive inheritance underlying classic Bethlem myopathy phenotypes (PMID:19884007).

The integration of genetic and functional data across over 100 probands from >20 families, with consistent segregation and concordant in vitro assays, supports a definitive gene–disease relationship. Detailed genotype–phenotype correlations and mechanistic insights inform diagnostic sequencing, genetic counseling, and targeted antisense or genome‐editing therapies.

Key take‐home: COL6A1 mutations cause autosomal dominant Bethlem myopathy via dominant‐negative effects on collagen VI assembly, and molecular diagnosis enables precise prognostic counseling and therapeutic development.

References

• Muscle & nerve • 2002 • Novel COL6A1 splicing mutation in a family affected by mild Bethlem myopathy. PMID:11932968
• Neurology • 2005 • Detection of common and private mutations in the COL6A1 gene of patients with Bethlem myopathy. PMID:15955946
• Annals of neurology • 2007 • Molecular consequences of dominant Bethlem myopathy collagen VI mutations. PMID:17886299
• European journal of paediatric neurology • 2002 • Muscle MRI findings in a three-generation family affected by Bethlem myopathy. PMID:12401455

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