Three arginine to cysteine substitutions 4 in the pro-alpha (I)-collagen chain cause Ehlers-Danlos syndrome with a propensity to arterial rupture in early adulthood

Mutations in the COL1A1 and COL1A2 genes, encoding the pro alpha 1 and 2 chains of type I collagen, cause osteogenesis imperfecta (OI) or Ehlers Danlos syndrome (EDS) arthrochalasis type. Although the majority of missense mutations in the collagen type I triple helix affect glycine residues in the Gly-Xaa-Yaa repeat, few nonglycine substitutions have been reported. Two arginine to-cysteine substitutions in the alpha 1 (1) collagen chain are associated with classic EDS [R134C (p.11312C)] or autosomal dominant Caffey disease with mild EDS features [R836C (p.R1014C)]. Here we show alpha 1 (I) R to-C substitutions in three unrelated patients who developed iliac or femoral dissection in early adulthood. In addition, manifestations of classic EDS in Patient I [c.934C > T, R134C (p.R312C); X-position] or osteopenia in Patients 2 [c.1720C > T, R396C (p.R574C); Y-position] and 3 [c.3277C > T; R915C (p.R1093C); Y-position] are seen. Dermal fibroblasts from the patients produced disulfide,bonded alpha 1 (1),dimers in similar to 20% of type I collagen, which were efficiently secreted into the medium in case of the R396C and R915C substitution. Theoretical stability calculations of the collagen type I heterotrimer and thermal denaturation curves of monomeric mutant alpha 1(I) collagen chains showed minor destabilization of the collagen helix. However, dimers were shown to be highly unstable. The R134C and R396C caused delayed procollagen processing by N-proteinase. Ultrastructural findings showed collagen fibrils with variable diameter and irregular interfibrillar spaces, suggesting disturbed collagen fibrillogenesis. Our findings demonstrate that R-to-C substitutions in the alpha 1 (I) chain may result in a phenotype with propensity to arterial rupture in early adulthood. This broadens the phenotypic range of nonglycine substitutions in collagen type I and has important implications for genetic counseling and follow-up of patients carrying this type of mutation