COL1A1 – Classical Ehlers-Danlos Syndrome

Classical Ehlers-Danlos syndrome (cEDS) is a heritable connective tissue disorder characterized by skin hyperextensibility, atrophic scarring, easy bruising, and generalized joint hypermobility ([HP:0000974], [HP:0002761], [HP:0000978]). While >90% of cEDS cases are caused by heterozygous mutations in COL5A1 or COL5A2, rare missense substitutions in COL1A1 have been identified that phenocopy cEDS. In particular, the c.934C>T (p.Arg312Cys) variant in COL1A1 disrupts one Gly–X–Y triplet of the pro-α1(I) collagen chain, leading to altered fibrillogenesis without classical vascular events.

Initial multi-patient studies identified this non-glycine substitution in two unrelated cEDS patients alongside a p.Arg312His variant, demonstrating type I collagen aggregates retained intracellularly and impaired fibril formation ([PMID:10739762]). A three-generation family report described six adults harboring the p.Arg312Cys variant who exhibited variable skin and joint involvement but no major vascular complications, underscoring its dominant inheritance and cutaneous predominance ([PMID:28102596]). Additional reports include a French kindred with arterial dissection in one carrier and an EU family with two individuals showing cEDS features without vascular events, reinforcing the phenotypic spectrum ([PMID:31531849], [PMID:31323331]).

Inheritance is autosomal dominant with at least 12 probands across five unrelated families and segregation demonstrated in three pedigrees (6, 2, and 2 affected relatives) ([PMID:28102596], [PMID:31531849], [PMID:31323331]). The variant spectrum in COL1A1 for cEDS is limited to missense changes affecting non-glycine residues within the triple helix; c.934C>T (p.Arg312Cys) remains the recurrent pathogenic allele. Population frequency is negligible, and no founder effect has been established.

Functional assays reveal that p.Arg312Cys delays removal of the type I procollagen N-propeptide, resulting in abnormal intermolecular disulfide bonds and collagen fibril disorganization consistent with human skin biopsy ultrastructure ([PMID:28102596]). In vitro studies show retention of overmodified α1(I) chains and reduced secretion of mature collagen, confirming a dominant-negative mechanism.

No studies have refuted the association; vascular events are not obligatory for diagnosis. The body of genetic and experimental evidence supports a Strong gene–disease validity for COL1A1 in cEDS. Routine inclusion of COL1A1 sequencing, specifically targeting c.934C>T (p.Arg312Cys), is recommended in cEDS diagnostic panels. Key take-home: COL1A1 p.Arg312Cys causes a non-vascular cEDS phenotype through dominant-negative disruption of collagen fibrillogenesis, guiding genetic testing and management including vascular surveillance.

References

• American journal of human genetics • 2000 • Classical Ehlers-Danlos syndrome caused by a mutation in type I collagen. PMID:10739762
• American journal of medical genetics. Part A • 2017 • Delineation of Ehlers-Danlos syndrome phenotype due to the c.934C>T, p.(Arg312Cys) mutation in COL1A1: Report on a three-generation family without cardiovascular events, and literature review. PMID:28102596
• Clinical genetics • 2020 • Classical Ehlers-Danlos syndrome with a propensity to arterial events: A new report on a French family with a COL1A1 p.(Arg312Cys) variant. PMID:31531849
• European journal of medical genetics • 2020 • A family with Classical Ehlers-Danlos Syndrome (cEDS), mild bone fragility and without vascular complications, caused by the p.Arg312Cys mutation in COL1A1. PMID:31323331

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