交界性大疱性表皮松解症的分子机制:Col15区域突变降低了XVII型胶原的热稳定性  

Molecular mechanisms of junctional epidermolysis bullosa: Col15 domain mutations decrease the thermal stability of collagen XVII

作　　者：Visnen L. Has C. Franzke C. K. Tasanen 罗素菊 

机构地区：[1]Department of Dermatology, University of Oulu, Aapistie 5 A, FIN- 90230, Oulu, Finland

出　　处：《世界核心医学期刊文摘（皮肤病学分册）》2006年第9期12-13,共2页Digest of the World Core Medical JOurnals:Dermatology

摘　　要：Mutations in the collagen XVII gene, COL17A1, are associated with junctional epidermolysis bullosa. Most COL17A1 mutations lead to a premature termination codon (PTC), whereas only a few mutations result in amino acid substitutions or deletions. We describe here two novel glycine substitutions, G609D and G612R, and a splice site mutation resulting in a deletion of three Gly-X-Yamino acid triplets. In order to investigate the molecular pathomechanisms of non-PTC mutations, G609D and G612R and two previously known substitutions, G627V and G633, and deletion of the amino acids 779- 787 were introduced into recombinant collagen XVII. The thermal stability of the mutated collagens was assessed using trypsin digestions at incremental temperatures. All the four glycine substitutions significantly destabilized the ectodomain of collagen XVII, which manifested as 16° C- 20° C lower Tm (midpoint of the helix-to-coil transition). These results were supported by secondary structure predictions, which suggested interruptions of the collagenous triple helix within the largest collagenous domain, Col15. In contrast, deletion of the three full Gly-XY triplets, amino acids 779- 787, had no overall effect on the stability of the ectodomain, as the deletion was in register with the triplet structure and also generated compensatory changes in the NC15 domain.Mutations in the collagen ⅩⅦ gene, COL17A1, are associated with junctional epidermolysis bullosa. Most COL17A1 mutations lead to a premature termination codon （PTC）, whereas only a few mutations result in amino acid substitutions or deletions. We describe here two novel glycine substitutions, G609D and G612R, and a splice site mutation resulting in a deletion of three Gly-X-Yamino acid triplets. In order to investigate the molecular pathomechanisms of non-PTC mutations, G609D and G612R and two previously known substitutions, G627V and G633, and deletion of the amino acids 779 - 787 were introduced into recombinant collagen ⅩⅦ. The thermal stability of the mutated collagens was assessed using trypsin digestions at incremental temperatures. All the four glycine substitutions significantly destabilized the ectodomain of collagen ⅩⅦ, which manifested as 16℃- 20℃ lower Tm （midpoint of the helix-to-coil transition） . These results were supported by secondary structure predictions, which suggested interruptions of the collagenous triple helix within the largest collagenous domain, Co115. In contrast, deletion of the three full Gly-XY triplets, amino acids 779 -787, had no overall effect on the stability of the ectodomain, as the deletion was in register with the triplet structure and also generated compensatory changes in the NC15 domain.

关 键 词：大疱性表皮松解症 Ⅶ型胶原 基因突变 热稳定性 交界性 分子机制 氨基酸缺失 分子病理机制 

分 类 号：R758.59[医药卫生—皮肤病学与性病学]