Type I osteogenesis imperfecta: a nonfunctional allele for pro alpha 1 (I) chains of type I procollagen.

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Abstract
Type I osteogenesis imperfecta (OI) is a dominantly inherted disease characterized clinically by bone fractures during childhood, blue sclerae and frequent hearing loss accompanied by a decreased content of type I collagen in bone and skin. Cultured skin fibroblasts from 3 individuals affected with the disease produce half-normal levels of type I procollagen, a disulfide-bonded trimer that contains 2 pro.alpha.1(I) chains and 1 pro.alpha.2(I) chain. In normal cells, pro.alpha.1(I) and pro.alpha.2(I) are synthesized in a 2:1 ratio and only assembled molecules are secreted. The OI cells contain equimolar amounts of pro.alpha.1(I) and pro.alpha.2(I), which suggests that trimer assembly and secretion are limited by the level of pro.alpha.1(I) synthesis. The extra pro.alpha.2(I) in the OI cells is in a nondisulfide-bonded configuration and is not secreted but apparently contributes to an increased level of intracellular degradation. Decreased production of type I procollagen in these patients is the result of decreased synthesis of pro.alpha.1(I) procollagen is evidently determined by the conformation of the chains rather than the ratio in which they are synthesized, that molecules containing more than a single pro.alpha.2(I) chain are not assembled, and that the production of this heteropolymeric molecule may be effectively regulated by controlling the synthesis of only one of the subunits.