SUBSTITUTION OF GLYCINE-661 BY SERINE IN THE ALPHA-1(I) AND ALPHA-2(I) CHAINS OF TYPE-I COLLAGEN RESULTS IN DIFFERENT CLINICAL AND BIOCHEMICAL PHENOTYPES

We have characterised a point mutation causing the substitution of ser ine for glycine at position 661 of the alpha 1(I) chain of type I coll agen in a child with a severe form of osteogenesis imperfecta. An iden tical glycine substitution in the alpha 2(I) chain was previously dete cted in a woman with post-menopausal osteoporosis, Two of her sons wer e heterozygous for the mutation and the third son was homozygous as a result of uniparental isodisomy. Biochemical profiles of the type I co llagen 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 alp ha 1(I) mutation but mild in the patients with the alpha 2(I) mutation , being slightly less evident in the heterozygote than in the homozygo te. Investigation of the melting curves of the mutant collagen trimers in all three patients showed the same slight decrease in thermal stab ility and, hence, a lack of correlation with phenotypic severity, In c ontrast, the degree of overmodification of the collagen alpha chains w as correlated with the phenotypic severity. The clinical observations in these patients illustrate the possibly predominant role of mutation s in the collagen alpha 1(I) chains over the same mutations in the alp ha 2(I) chains in determining the clinical outcome.