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COL4A1 – Muscular dystrophy-dystroglycanopathy, type A

Muscle-eye-brain disease (MEB), a subtype of muscular dystrophy-dystroglycanopathy, type A, is characterized by ocular dysgenesis, neuronal migration defects, and congenital muscular dystrophy. While glycosylation genes are classically implicated, PLoS Genetics identified heterozygous COL4A1 variants in two unrelated patients ([PMID:21625620]). The variant c.4423T>C (p.Tyr1475His) affects a conserved triple-helix residue, disrupting secretion and leading to intracellular collagen IV accumulation.

In heterozygous Col4a1 mutant mice, ocular malformations, neuronal localization defects, and myopathy mirrored the human MEB/WWS spectrum without dystroglycan hypoglycosylation, establishing a distinct dominant-negative mechanism ([PMID:21625620]). These models confirmed pathogenicity through histological, biochemical, and molecular assays.

Key Take-home: Autosomal dominant COL4A1 missense variants can underlie muscular dystrophy-dystroglycanopathy, type A presenting as MEB, informing diagnostic testing and therapeutic target exploration.

References

  • PLoS Genetics • 2011 • COL4A1 mutations cause ocular dysgenesis, neuronal localization defects, and myopathy in mice and Walker-Warburg syndrome in humans. PMID:21625620

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

2 probands with heterozygous variants in COL4A1 ([PMID:21625620]); no familial segregation

Genetic Evidence

Limited

2 unrelated probands ([PMID:21625620]) with heterozygous missense COL4A1 variants

Functional Evidence

Moderate

Heterozygous Col4a1 mouse model recapitulates MEB/WWS phenotypes and shows collagen IV secretion defects ([PMID:21625620])