Nuytinck L, Dalgleish R, Spotila L, Renard J P, Van Regemorter N, De Paepe A
Centre for Medical Genetics, University Hospital Ghent, Belgium.
Hum Genet. 1996 Mar;97(3):324-9. doi: 10.1007/BF02185764.
We have characterised a point mutation causing the substitution of serine for glycine at position 661 of the alpha1(I) chain of type I collagen in a child with a severe form of osteogenesis imperfecta. An identical glycine substitution in the alpha2(I) chain was previously detected in a woman with post-menopausal osteoporosis. Two of her sons were heterozygous for the mutation and the third son was homozygous as a result of uniparental isodisomy. Biochemical profiles of the type I collagen heterotrimers were studied in each of the patients and compared with a control. Medium and cell-layer collagens were overmodified in all patients. Overmodification was obvious in the patient with the alpha 1(I) mutation but mild in the patients with the alpha 2(I) mutation, being slightly less evident in the heterozygote than in the homozygote. Investigation of the melting curves of the mutant collagen trimers in all three patients showed the same slight decrease in thermal stability and, hence, a lack of correlation with phenotypic severity. In contrast, the degree of overmodification of the collagen alpha chains was correlated with the phenotypic severity. The clinical observations in these patients illustrate the possibly predominant role of mutations in the collagen alpha1(I) chains over the same mutations in the alpha2(I) chains in determining the clinical outcome.
我们已对一名患有严重型成骨不全症儿童的Ⅰ型胶原蛋白α1（I）链第661位丝氨酸替代甘氨酸的点突变进行了特征分析。先前在一名绝经后骨质疏松症女性中检测到α2（I）链存在相同的甘氨酸替代。她的两个儿子为该突变的杂合子，第三个儿子因单亲二体性而成为纯合子。对每位患者的Ⅰ型胶原蛋白异源三聚体的生化特征进行了研究，并与对照进行比较。所有患者的中膜和细胞层胶原蛋白均过度修饰。α1（I）突变患者的过度修饰明显，但α2（I）突变患者的过度修饰较轻，杂合子中的过度修饰比纯合子稍不明显。对所有三名患者的突变胶原蛋白三聚体的熔解曲线进行研究，结果显示热稳定性同样略有下降，因此与表型严重程度缺乏相关性。相比之下，胶原蛋白α链的过度修饰程度与表型严重程度相关。这些患者的临床观察结果表明，在决定临床结局方面，胶原蛋白α1（I）链中的突变可能比α2（I）链中的相同突变起更主要的作用。
