COL6A2 – Ullrich congenital muscular dystrophy 1A

Ullrich congenital muscular dystrophy 1A (UCMD1A) is an autosomal recessive disorder caused by biallelic loss‐of‐function and structural mutations in the COL6A2 gene, encoding the α2 chain of collagen VI. Clinically, patients present from birth with generalized muscle weakness, proximal joint contractures and distal joint hyperlaxity, reflecting a primary defect in the link between the interstitium and basal lamina ([PMID:12297580]).

Genetic evidence for COL6A2 in UCMD1A includes a compound heterozygous proband with complete collagen VI deficiency on EM harboring two COL6A2 alleles ([PMID:12297580]), two unrelated patients with homozygous C-globular missense substitutions c.1870G>A (p.Glu624Lys) and c.2627G>C (p.Arg876Ser) ([PMID:20106987]), and at least three additional unrelated families with non-canonical splice-site and truncating variants in COL6A2 ([PMID:19309692]; [PMID:24801232]).

Inheritance is uniformly autosomal recessive, with no reported dominant segregation. To date, ≥6 unrelated probands have been described, spanning missense (e.g., c.1870G>A (p.Glu624Lys) ([PMID:20106987])), splice‐site (e.g., c.736-1G>C) and nonsense/frameshift (e.g., c.1096C>T (p.Arg366Ter)) variant classes.

Functional studies demonstrate that the Glu624Lys substitution moderately disrupts collagen VI secretion and network architecture, whereas Arg876Ser abolishes triple-helix assembly in patient fibroblasts ([PMID:20106987]). Minigene and quantitative RNA assays of non-canonical COL6A2 splice mutations reveal exon skipping and intron retention leading to in‐frame or truncated transcripts with reduced expression ([PMID:19309692]). Immunohistochemistry in patient biopsies shows markedly reduced collagen VI at the muscle basement membrane ([PMID:24801232]).

The pathogenic mechanism involves absence or structural disruption of collagen VI microfibrils, compromising extracellular matrix integrity and muscle fiber support. These data are concordant across cell, tissue and ultrastructural assays, mirroring the human phenotype.

Additional evidence includes comprehensive variant catalogs in multi-ethnic cohorts, but this exceeds the genetic scoring cap. Key take-home: COL6A2 mutation screening is essential for definitive diagnosis of UCMD1A and enables genetic counseling and eligibility for emerging collagen VI–targeted therapies.

References

• Neurology • 2002 • Ullrich disease: collagen VI deficiency: EM suggests a new basis for muscular weakness. PMID:12297580
• The Journal of Biological Chemistry • 2010 • Recessive COL6A2 C-globular missense mutations in Ullrich congenital muscular dystrophy: role of the C2a splice variant. PMID:20106987
• Human Mutation • 2009 • Identification and characterization of novel collagen VI non-canonical splicing mutations causing Ullrich congenital muscular dystrophy. PMID:19309692
• World Journal of Pediatrics • 2014 • Novel collagen VI mutations identified in Chinese patients with Ullrich congenital muscular dystrophy. PMID:24801232

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