COL6A2 – Ullrich congenital muscular dystrophy

Ullrich congenital muscular dystrophy (UCMD) is a severe collagen VI–related myopathy characterized by congenital muscle weakness, proximal joint contractures, distal hyperlaxity and progressive respiratory failure. Recessive mutations in COL6A2 have been repeatedly identified in UCMD patients, establishing COL6A2 as a key gene in disease etiology (PMID:16075202).

Genetic analyses show that UCMD often follows an autosomal recessive inheritance pattern. A prototypic case harbors a homozygous intronic variant, c.1117-10A>G, which activates cryptic splice acceptor sites causing exon 13 skipping and triggering nonsense-mediated mRNA decay, leading to markedly reduced COL6A2 transcript and collagen VI microfibril deficiency (PMID:16075202).

Large cohort studies have identified over 60 distinct pathogenic COL6A2 alleles — including missense, nonsense, splice-site and frameshift variants — across more than 100 unrelated probands. Segregation of compound heterozygous or homozygous variants has been documented in at least two affected sibling pairs, confirming recessive transmission and supporting strong genetic evidence (PMID:12011280).

Functional assays in patient fibroblasts and transfected cells demonstrate that COL6A2 loss-of-function mutations result in defective collagen VI assembly: mutant transcripts undergo decay, C-globular domain missense substitutions impair microfibril network formation, and secreted collagen VI is absent or mislocalized at the sarcolemma (PMID:12218063).

Mechanistically, COL6A2 pathogenic variants cause collagen VI haploinsufficiency when recessive or act dominantly via negative assembly effects when in-frame deletions occur. This underpins the clinical continuum from severe UCMD to milder Bethlem myopathy.

Integration of genetic, segregation and experimental data over ≥15 years supports a definitive gene-disease validity for COL6A2 in UCMD. Accurate molecular diagnosis enables carrier detection, prenatal testing and informs emerging antisense therapies targeting aberrant splicing.

Key Take-home: COL6A2 recessive mutations cause collagen VI deficiency in UCMD with definitive evidence, guiding diagnostic testing and therapeutic development.

References

• Human genetics | 2005 | A homozygous COL6A2 intron mutation causes in-frame triple-helical deletion and nonsense-mediated mRNA decay in a patient with Ullrich congenital muscular dystrophy. PMID:16075202
• Neurology | 2002 | Collagen VI involvement in Ullrich syndrome: a clinical, genetic, and immunohistochemical study. PMID:12011280
• The Journal of biological chemistry | 2002 | Effects on collagen VI mRNA stability and microfibrillar assembly of three COL6A2 mutations in two families with Ullrich congenital muscular dystrophy. PMID:12218063

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