Moderately severe osteogenesis imperfecta associated with substitutions of serine for glycine in the α1(I) chain of type I collagen

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Abstract
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 α1(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 α1(I) mRNA using RNA/RNA hybrids; it was demonstrated to be due to a G→A point mutation in one allele of α1(I), resulting in the substitution of serine for glycine 832. The second child is now 6½ years old, with the height of 1½‐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 α1(I) mRNA has also been studied by RNA hybrid analysis; there is a single G→A change in one α1(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 sub‐stitutions. 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.