COL5A1 – Ehlers-Danlos Syndrome

COL5A1 encodes the proα1(V) chain of type V collagen, a minor but critical regulator of heterotypic collagen fibril assembly in skin, joints, and other connective tissues. Classical Ehlers-Danlos syndrome (cEDS; MONDO:0020066) is characterized by skin hyperextensibility, joint hypermobility, easy bruising, and tissue fragility. Pathogenic COL5A1 variants underlie the autosomal dominant form of cEDS by disrupting collagen V synthesis or structure (PMID:8950675).

Genetic evidence supports a definitive association: over 200 unrelated probands have been reported, with more than 70 distinct Gly→X substitutions in the triple helix and over 30 null alleles leading to haploinsufficiency (PMID:22696272, PMID:10777716). Segregation in multigenerational families includes a four-generation kindred with a Cys→Ser substitution in the C-propeptide (PMID:9042913) and linkage in two British families (lod score 5.7; 14 affected relatives) (PMID:9499606).

Inheritance of cEDS due to COL5A1 is autosomal dominant, with heterozygous individuals displaying variable expressivity. A representative intronic splice-donor variant, c.3906+3G>T, causes in-frame exon skipping and incorporation of shortened α1(V) chains into collagen fibrils, resulting in irregular fibril outlines and disrupted matrix organization (PMID:8950675).

Functional assays demonstrate that COL5A1 haploinsufficiency lowers proα1(V) mRNA and protein levels in patient fibroblasts, causing abnormal collagen fibrillogenesis on electron microscopy. Novel N-propeptide splice-site mutations perturb exon order and yield aberrant transcripts that are secreted yet disrupt fibril diameter regulation (PMID:21611149). Animal and cell‐based models recapitulate the skin and vascular fragility seen in patients.

Although classic skin and joint features dominate, COL5A1 mutations have been associated with rare vascular events, including arterial dissection in cEDS patients with null alleles, underscoring the need for cardiovascular surveillance. No disputed or refuting studies of COL5A1 in cEDS have been reported.

In summary, the evidence for COL5A1 in classical Ehlers-Danlos syndrome is definitive, with robust genetic and functional data. Molecular testing for COL5A1 variants is essential for accurate diagnosis, family counseling, and management of skin, joint, and vascular complications. Key take-home: COL5A1 gene analysis should be a frontline test in individuals with cutaneous fragility, joint laxity, and familial cEDS features.

References

• Journal of medical genetics • 1996 • An exon skipping mutation of a type V collagen gene (COL5A1) in Ehlers-Danlos syndrome PMID:8950675
• American journal of human genetics • 1997 • Mutations in the COL5A1 gene are causal in the Ehlers-Danlos syndromes I and II PMID:9042913
• Clinical and experimental dermatology • 1997 • Genetic linkage to the collagen alpha 1 (V) gene (COL5A1) in two British Ehlers-Danlos syndrome families with variable type I and II phenotypes PMID:9499606
• American journal of human genetics • 2000 • COL5A1 haploinsufficiency is a common molecular mechanism underlying the classical form of EDS PMID:10777716
• PLoS One • 2011 • A novel splice variant in the N-propeptide of COL5A1 causes an EDS phenotype with severe kyphoscoliosis and eye involvement PMID:21611149
• Human mutation • 2012 • Comprehensive molecular analysis demonstrates type V collagen mutations in over 90% of patients with classic EDS and allows to refine diagnostic criteria PMID:22696272

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