Partial COL1A2 gene duplication produces features of osteogenesis imperfecta and Ehlers-Danlos syndrome type VII

Type I collagen is the most abundant structural protein in the mammalian bo dy. It exists as a heterotrimer of two subunits in the form [alpha 1(I)](2) alpha 2(I). Pathogenic mutations in COL1A1 and COL1A2, the genes that encod e the two subunits, cause a range of phenotype including mild to lethal for ms of osteogenesis imperfecta and a restricted set of Ehlers-Danlos syndrom e phenotypes. Lethal mutations usually result from missense mutations that disrupt the normal triple helical structure of the molecule. Multi-exon dup lication or deletion in type I collagen genes has rarely been observed and has generally resulted in a lethal or severe phenotype. We report a partial duplication in the COL1A2 gene that causes a relatively mild phenotype, de spite the addition of 477 amino acids to the triple helical domain of the p ro alpha 2(I) chain. The abnormal molecule is synthesized and secreted by c ultured dermal fibroblasts in a normal fashion. Electron microscopy of derm al tissue reveals small but otherwise near normal collagen fibrils. The gen e duplication occurred by mitotic sister chromatid exchange in the mother w ho is mosaic for the duplication allele. Examination of the abnormal sequen ce suggests a means by which the duplicated molecule could be processed and properly incorporated into mature collagen fibrils.