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COL6A3 encodes the α3 chain of type VI collagen, a critical component of the extracellular matrix in muscle and skin. Ullrich congenital muscular dystrophy (UCMD; MONDO:0000355) is characterized by early-onset muscle weakness, proximal joint contractures, distal joint hyperextensibility, and progressive respiratory compromise. Initial linkage and sequencing studies in a consanguineous family with three affected siblings established autosomal recessive inheritance of UCMD due to homozygous COL6A3 splice-donor mutations, demonstrating exon skipping, reduced collagen VI deposition, and an intermediate phenotype (PMID:11992252).
Subsequent case reports expanded the mutation spectrum to include one patient with a homozygous nonsense mutation (c.1393C>T (p.Arg465Ter)) and another with homozygous nonsense (c.7024C>T (p.Arg2342Ter)), both causing absent collagen VI in muscle and severe UCMD (PMID:11992252). More recently, de novo heterozygous splice-site variants (c.6210+1G>A) were identified in classical UCMD presentations, indicating autosomal dominant mechanisms can also underlie UCMD (PMID:35832501).
In multi-patient studies, immunohistochemical analysis of 15 UCMD patients revealed collagen VI deficiency linked to COL6A3 in 40% of cases by haplotype and linkage, underscoring genetic heterogeneity yet common involvement of COL6A3 in UCMD (PMID:12011280). Targeted NGS in cohorts confirmed COL6A3 pathogenic variants in both recessive and dominant contexts, accounting for a significant fraction of UCMD cases and highlighting variable expressivity.
Inheritance of COL6A3-related UCMD is predominantly autosomal recessive, but de novo dominant splice mutations have been documented. To date, at least seven unrelated probands harbor three loss-of-function (two nonsense, one in-frame pseudoexon) and two splice-site variants, with segregation in multiple families and de novo occurrence. A representative pathogenic variant is c.7024C>T (p.Arg2342Ter), which truncates the collagen VI α3 chain and abolishes matrix assembly.
Functional assays have confirmed the pathogenicity of COL6A3 variants: splice-site and nonsense mutations lead to intracellular misfolding, degradation of mutant α3(VI) domains, loss of extracellular collagen VI network integrity, and impaired filament organization in patient fibroblasts (PMID:15965965; PMID:11992252). These defects mirror the clinical phenotype of UCMD, supporting a loss-of-function mechanism.
Collectively, the genetic and experimental data support a Strong clinical validity for the COL6A3–UCMD association. COL6A3 mutations explain a substantial subset of UCMD cases, enabling accurate diagnosis, genetic counseling, and informing emerging splice-modulating therapies. Key take-home: COL6A3 pathogenic variants cause UCMD via recessive and de novo dominant mechanisms, leading to definitive collagen VI deficiency and a clinically actionable genotype–phenotype correlation.
Gene–Disease AssociationStrongSeven unrelated probands (five recessive, two de novo dominant), segregation in consanguineous family, concordant functional data Genetic EvidenceModerateSeven pathogenic COL6A3 variants (three loss-of-function, two splice-site) identified in multiple families including de novo occurrences Functional EvidenceModerateMutant α3(VI) misfolding and assembly failure in cell and tissue assays, consistent with human UCMD phenotype |