COL3A1 – Vascular Ehlers-Danlos Syndrome

COL3A1 encodes the pro-alpha1 chain of type III procollagen and is associated with autosomal dominant vascular Ehlers-Danlos syndrome (vEDS). Mutations such as the splice-donor variant c.1347+1G>A disrupt normal RNA splicing, leading to exon 20 skipping and markedly reduced type III collagen production ((PMID:2349939)).

Clinical genetic studies have identified COL3A1 variants in over 135 unrelated index patients and 199 affected relatives, establishing a definitive gene–disease link. In a cohort of 135 index cases, 33 distinct splice-junction mutations and glycine substitutions segregated with arterial and visceral ruptures in multigenerational pedigrees ((PMID:10706896); (PMID:9399899)).

The variant spectrum includes glycine substitutions (e.g., c.610G>A (p.Gly204Ser) in a fatal adolescent case of bowel and vascular rupture (PMID:9841712)), canonical splice-site mutations (c.2931+1G>A)(PMID:1757960), frameshifts, exon deletions, and deep-intronic changes. Recurrent alleles have been observed in population-specific founder cohorts, and null alleles arising from PTCs cause haploinsufficiency with a milder, later-onset phenotype.

Affected individuals present with medium-vessel aneurysms and dissections (HP:0002647), ascending aortic aneurysm (HP:0004970), spontaneous colon rupture, translucent thin skin (HP:0000963), easy bruising (HP:0000978), joint hypermobility (HP:0001382), and uterine rupture in pregnancy. Penetrance is high by age 40, with >80% experiencing major complications ((PMID:10706896)).

Functional studies demonstrate that allele-specific siRNA targeting mutant COL3A1 restores normal fibril architecture in patient fibroblasts, alleviates ER stress, and normalizes ECM organization ((PMID:22038052)). Col3a1 haploinsufficient mice exhibit reduced trabecular bone volume and impaired osteoblast differentiation, corroborating a loss-of-function mechanism ((PMID:24626604)). Transcriptome profiling of vEDS fibroblasts reveals disassembly of fibrillins and altered expression of ER-homeostasis genes ((PMID:29346445)).

No studies have refuted the COL3A1–vEDS association. Together, robust segregation data, a wide variant spectrum, and concordant in vitro and in vivo functional evidence meet ClinGen criteria for a definitive gene–disease relationship. Genetic testing of COL3A1 informs early diagnosis, risk stratification, and family counseling in vEDS.

References

• American journal of human genetics • 1990 • Inheritance of an RNA splicing mutation (G+1 IVS20) in the type III procollagen gene (COL3A1) in a family having aortic aneurysms and easy bruisability: phenotypic overlap between familial arterial aneurysms and Ehlers-Danlos syndrome type IV PMID:2349939
• The New England journal of medicine • 2000 • Clinical and genetic features of Ehlers-Danlos syndrome type IV, the vascular type PMID:10706896
• American journal of human genetics • 1997 • Splicing defects in the COL3A1 gene: marked preference for 5′ (donor) splice-site mutations in patients with exon-skipping mutations and Ehlers-Danlos syndrome type IV PMID:9399899
• Pediatric and developmental pathology • 1999 • Multiple vascular and bowel ruptures in an adolescent male with sporadic Ehlers-Danlos syndrome type IV PMID:9841712
• FASEB journal • 2012 • Allele-specific siRNA knockdown as a personalized treatment strategy for vascular Ehlers-Danlos syndrome in human fibroblasts PMID:22038052
• Calcified tissue international • 2014 • Type III collagen regulates osteoblastogenesis and the quantity of trabecular bone PMID:24626604
• PLoS One • 2018 • Transcriptome analysis of skin fibroblasts with dominant negative COL3A1 mutations provides molecular insights into the etiopathology of vascular Ehlers-Danlos syndrome PMID:29346445

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