Substitution of glycine-661 by serine in the α1(I) and α2(1) chains of type I collagen results in different clinical and biochemical phenotypes
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- Nuytinck, L., Dalgleish, R., Spotila, L. et al. Hum Genet (1996) 97: 324. doi:10.1007/BF02185764
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We have characterised a point mutation causing the substitution of serine for glycine at position 661 of the α1(I) chain of type I collagen in a child with a severe form of osteogenesis imperfecta. An identical glycine substitution in the α2(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 α1(I) mutation but mild in the patients with the α2(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 α1(I) chains over the same mutations in the α2(I) chains in determining the clinical outcome.