前α (I)-胶原链中的三个精氨酸到半胱氨酸的取代导致成年早期动脉破裂倾向的ehers - danlos综合征。
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马菲特F, Symoens S, De Backer J, Hermanns-Le T, Sakalihasan N, Lapiere CM, Coucke P, De Paepe A
前α (I)-胶原链中的三个精氨酸到半胱氨酸的取代导致成年早期动脉破裂倾向的ehers - danlos综合征。
植物学报，2007,28(4):387-95。
- PubMed ID
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17211858 (PubMed视图]
- 摘要
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编码I型胶原蛋白proalpha1和2链的COL1A1和COL1A2基因突变可导致成骨不全症(OI)或ehers - danlos综合征(EDS)型关节关节病。尽管I型胶原蛋白三螺旋中的大多数错义突变影响Gly-Xaa-Yaa重复序列中的甘氨酸残基，但很少有非甘氨酸取代的报道。α 1(I)-胶原蛋白链上的两个精氨酸-半胱氨酸替换与典型EDS [R134C (p.R312C)]或常染色体显性Caffey病伴轻度EDS [R836C (p.R1014C)]相关。在这里，我们展示了三个在成年早期发生髂或股夹层的无关患者的α 1(I) R-to-C替换。此外，患者1的典型EDS表现[c.1053C>T;R134C (p.R312C);2例患者x位[c]或骨质减少[c];R396C (p.R574C);y位]和3 [c.3396C>T;R915C (p.R1093C); Y-position] are seen. Dermal fibroblasts from the patients produced disulfide-bonded alpha1(I)-dimers in approximately 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 alpha1(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 alpha1(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.