COL6A2 – Bethlem Myopathy

COL6A2 encodes the α2(VI) chain of type VI collagen, mutations in which cause Bethlem myopathy (BM; [MONDO:0008029]), a slowly progressive collagen VI–related dystrophy characterized by proximal muscle weakness, joint contractures, keloids, and follicular hyperkeratosis. BM is part of a spectrum ranging from mild BM to severe Ullrich congenital muscular dystrophy, unified by disrupted collagen VI assembly and extracellular matrix integrity.

Inheritance of BM is predominantly autosomal dominant, though autosomal recessive cases have been documented. Two adult siblings with classic BM carried compound heterozygous COL6A2 mutations (c.1770delG and p.Arg830Trp), confirming recessive inheritance ([PMID:19884007]). A Saudi family with two affected siblings segregated a homozygous splice-site variant c.1817-3C>G in COL6A2, with asymptomatic heterozygous parents, further supporting autosomal recessive transmission ([PMID:39596604]). Conversely, dominant glycine substitutions and exon-skipping variants in COL6A2 underlie typical BM pedigrees with multi-generational segregation, illustrating both inheritance modes.

Case series and cohorts have identified numerous COL6A2 variants in BM. In a Chinese cohort of 60 collagen VI-related myopathy probands (20 BM, 40 UCMD), 33 pathogenic COL6A2 alleles were found, including missense, nonsense, and splice mutations ([PMID:29419890]). In an autosomal recessive BM family, two novel pathogenic variants—nonsense p.Gln889Ter and in-frame insertion p.Pro260_Lys261insProPro—co-segregated in two adult siblings with reduced collagen VI secretion ([PMID:31471117]). A representative intronic variant, c.1861G>A (p.Asp621Asn), exemplifies the spectrum of missense changes disrupting triple-helix stability.

Functional studies demonstrate that COL6A2 mutations impair both intracellular assembly and extracellular microfibrillar network formation. Patient fibroblasts harboring recessive p.Gln889Ter and p.Pro260_Lys261insProPro show diminished collagen VI secretion and aberrant microfibril assembly ([PMID:31471117]). Tendon biopsies from a UCMD patient with compound heterozygous COL6A2 mutations revealed altered fibrillogenesis and extracellular matrix disorganization, implicating impaired collagen VI web formation in pathogenesis ([PMID:27375477]).

Some variants modulate phenotype severity. The p.Arg830Trp substitution in compound heterozygosity with an exon-skipping allele resulted in classic BM rather than Ullrich dystrophy, suggesting residual chain function ameliorates disease ([PMID:19884007]). No studies to date have refuted the COL6A2–BM association.

Altogether, over 60 unrelated BM probands harboring diverse COL6A2 variants, segregation data in multiple families, and concordant functional assays establish a definitive gene–disease relationship. COL6A2 genetic testing informs diagnosis, inheritance risk, and potential eligibility for splice-modulating and other targeted therapies.

Key Take-home: COL6A2 variants cause definitive Bethlem myopathy through dominant or recessive disruption of collagen VI assembly, warranting inclusion in diagnostic panels and guiding therapeutic development.

References

• Neuromuscular disorders : NMD • 2009 • Autosomal recessive inheritance of classic Bethlem myopathy. PMID:19884007
• Neuromuscular disorders : NMD • 2019 • Autosomal recessive Bethlem myopathy: A clinical, genetic and functional study. PMID:31471117
• Clinical genetics • 2018 • Genetic and clinical findings in a Chinese cohort of patients with collagen VI-related myopathies. PMID:29419890
• Genes • 2024 • Segregation of the COL6A2 Variant (c.1817-3C>G) in a Consanguineous Saudi Family with Bethlem Myopathy. PMID:39596604
• Frontiers in aging neuroscience • 2016 • Tendon Extracellular Matrix Alterations in Ullrich Congenital Muscular Dystrophy. PMID:27375477

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