COL5A2 – Ehlers-Danlos syndrome

COL5A2 encodes the alpha-2 chain of type V collagen, a minor fibrillar collagen essential for heterotypic fibril assembly. Heterozygous variants in COL5A2 underlie an autosomal dominant form of classical Ehlers-Danlos syndrome (cEDS), characterized by skin hyperextensibility, joint hypermobility and tissue fragility (PMID:9783710).

Initial evidence came from a single family in which all three affected members carried a glycine substitution in the triple-helical domain (c.3445G>C (p.Gly1149Arg)), absent in 50 controls. Cultured fibroblasts from an affected individual exhibited abnormal type V collagen synthesis, and haplotype analysis excluded COL5A1 as the locus (PMID:9783710). Two additional mono-allelic glycine substitutions (c.682G>A (p.Gly228Arg) in a 9-year-old with classical EDS features and c.3617G>A (p.Gly1206Glu) in a 14-year-old with scoliosis and hypotonia) further support pathogenicity (PMID:27656288; PMID:36447672).

A comprehensive cohort study of 126 clinically defined cEDS patients identified 93 with type V collagen defects, of which 13 harbored structural COL5A2 mutations, all glycine substitutions within the triple helix, confirming this gene’s major role in >90% of classical EDS cases meeting Villefranche criteria (PMID:22696272).

Beyond missense changes, a de novo synonymous variant (c.1977G>A (p.Pro659=)) was shown by RT-PCR to induce exon 29 skipping, yielding an in-frame deletion of the N-propeptide and supporting splice-altering synonymous mutations as pathogenic (PMID:33834621).

Mechanistically, glycine substitutions disrupt the tight triple-helix registry, acting in a dominant-negative manner. Functional assays—including fibroblast collagen synthesis and transcript analysis—are concordant with the human phenotype, demonstrating deficient type V collagen and aberrant fibrillogenesis (PMID:9783710; PMID:33834621). No large-scale conflicting studies have been reported.

Overall, evidence from 19 probands (3 familial segregations and 13 cohort cases) with heterozygous structural and splice-altering COL5A2 variants, alongside robust functional data, supports a Strong gene-disease association for autosomal dominant cEDS. COL5A2 genetic testing is clinically actionable for diagnostic confirmation and family counseling.

Key Take-home: Heterozygous COL5A2 variants cause a dominant-negative classical Ehlers-Danlos syndrome, guiding molecular diagnosis and management.

References

• Journal of medical genetics • 1998 • A single base mutation in COL5A2 causes Ehlers-Danlos syndrome type II. PMID:9783710
• Human genome variation • 2016 • A novel missense mutation of COL5A2 in a patient with Ehlers-Danlos syndrome. PMID:27656288
• Medicine • 2019 • A case of Ehlers-Danlos syndrome presenting with widened atrophic scars of forehead, elbow, knee, and pretibial area: A case report. PMID:31517854
• Clinical case reports • 2022 • Classical Ehlers-Danlos syndrome with severe kyphoscoliosis due to a novel pathogenic variant of COL5A2. PMID:36447672
• 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
• Molecular genetics & genomic medicine • 2021 • Clinical and genetic analysis of classical Ehlers-Danlos syndrome patient caused by synonymous mutation in COL5A2. PMID:33834621

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