OSTEOGENESIS IMPERFECTA TYPE-III - MUTATIONS IN THE TYPE-I COLLAGEN STRUCTURAL GENES, COL1A1 AND COL1A2, ARE NOT NECESSARILY RESPONSIBLE

Most forms of osteogenesis imperfecta are caused by dominant mutations in either of the two genes, COL1A1 and COL1A2, that encode the proalp ha1(I) and proalpha2(I) chains of type I collagen, respectively. Howev er, a severe, autosomal recessive form of OI type III with a comparati vely high frequency has been recognised in the black populations of so uthern Africa. We performed linkage analyses in eight OI type III fami lies using RFLPs associated with the COL1A1 and COL1A2 loci to determi ne whether mutations in the genes for type I collagen were responsible for this form of OI. Recombination between the OI phenotype and polym orphic markers at both loci was shown in three of the eight families i nvestigated. The combined lod scores for the eight families were -10.6 for COL1A1 and -11.2 for COL1A2. Further, we examined the type I proc ollagen produced by skin fibroblast cultures derived from 15 affected and 12 unaffected subjects from the above eight families plus one furt her family. We found no evidence for defects in the synthesis, structu re, secretion, or post-translational modification of the chains of typ e I procollagen produced by any of the family members. These results s uggest that mutations within or near the type I collagen structural ge nes are not responsible for this form of OI.