MODERATELY SEVERE OSTEOGENESIS IMPERFECTA ASSOCIATED WITH SUBSTITUTIONS OF SERINE FOR GLYCINE IN THE ALPHA-1(I) CHAIN OF TYPE-I COLLAGEN

We have examined the type I collagen protein, RNA, and cDNA of 2 children with moderately severe (type IV) osteogenesis imperfecta (OI). They have in common a non-lethal form of OI with ambulatory potential, over-modification of type I collagen protein, and a substitution of serine for glycine in the collagen chain produced by one alpha1(I) allele. The first child (Marini et al.: J Biol Chem 264:11893-11900,1989) is now 7 years old, with the height of a 3-year-old. Her course includes significant remodeling of lower long bones and 4 femur fractures. She walks independently. A mishmatch was detected in her alpha1(I) mRNA using RNA/RNA hybrids; it was demonstrated to be due to a G-->A point mutation in one allele of alpha1(I), resulting in the substitution of serine for glycine 832. The second child is now 6 1/2 years old, with the height of 1 1/2-year-old. Her history includes significant bowing of femurs and tibias, 6 femur fractures, S-curve scoliosis, compression of all lumbar vertebrae, and limited short-distance walking with braces. Her alpha1(I) mRNA has also been studied by RNA hybrid analysis; there is a single G-->A change in one alpha1(I) allele causing the substitution of serine for gly 352. Both children have moderately severe OI. However, the serine substitution at gly 352 is associated with a more severe phenotype then is the serine substitution at gly 832. Compared to substitutions described in other cases of OI, the serine 352 is located in the middle of a cluster of cysteine substitutions associated with non-lethal OI. The ser 832 is located near another non-lethal substitution of serine for glycine but is otherwise flanked by lethal substitutions. These data support a model of OI cause in which crucial and non-crucial regions are interspersed along the type I collagen chain. Whether a mutation located in a particular region causes OI type II or OI type IV would then depend on the importance of that region for the interaction of type I collagen with other matrix components or for intracellular processing.