Mutations of COMP cause two clinically distinct disorders: pseudo-achondroplasia and multiple epiphyseal dysplasia. Both are inherited as autosomal dominant disorders, have onset after birth, and are dominated by osteoarthritis of hips and knees. Dwarfism is severe and skeletal deformities are common in pseudoachondroplasia.
Cartilage collagens and COMP are multimeric molecules, that is, they are composed of multiple subunits, three for collagens and five for COMP. Like a square wheel on a car, the products of mutant alleles interfere functionally with the products of normal alleles when they combine during molecular assembly, a so-called dominant negative effect. Most collagen mutations are thought to act through this mechanism to reduce the number of collagen molecules in cartilage matrix, which in turn alters the ability of cartilage to function as a template for bone growth.
Similar types of mutations occur in genes encoding type I collagen, which is the principal matrix protein of bone. These mutations lead to osteogenesis imperfecta (OI), which is a spectrum of disorders of varying severity. The hallmark of OI is bone fractures, although patients often have blue sclerae (the "whites" of the eye), fragile skin, and dental problems that reflect the widespread distribution of type I collagen in many connective tissues.
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