Abstract
Type I procollagen is a heterotrimer composed of two proalpha1(I) chains and one proalpha2(I) chain, encoded by the COL1A1 and COL1A2 genes, respectively. Mutations in these genes usually lead to dominantly inherited forms of osteogenesis imperfecta (OI) by altering the triple helical domains, but a few affect sequences in the proalpha1(I) C-terminal propeptide (C-propeptide), and one, which has a phenotype only in homozygotes, alters the proalpha2(I) C-propeptide. Here we describe four dominant mutations in the COL1A2 gene that alter sequences of the proalpha2(I) C-propeptide in individuals with clinical features of a milder form of the disease, OI type IV. Three of the four appear to interfere with disulfide bonds that stabilize the C-propeptide conformation and its interaction with other chains in the trimer. Cultured cells synthesized proalpha2(I) chains that were slow to assemble with proalpha1(I) chains to form heterotrimers and that were retained intracellularly. Some alterations led to the uncharacteristic formation of proalpha1(I) homotrimers. These findings show that the C-propeptide of proalpha2(I), like that of the proalpha1(I) C-propeptide, is essential for efficient assembly of type I procollagen heterotrimers. The milder OI phenotypes likely reflect a diminished amount of normal type I procollagen, small populations of overmodified heterotrimers, and proalpha1(I) homotrimers that are compatible with normal skeletal growth.
Highlights
Type I procollagen is a heterotrimer composed of two pro␣1(I) chains and one pro␣2(I) chain, encoded by the COL1A1 and COL1A2 genes, respectively
Mutations in these genes usually lead to dominantly inherited forms of osteogenesis imperfecta (OI) by altering the triple helical domains, but a few affect sequences in the pro␣1(I) C-terminal propeptide (C-propeptide), and one, which has a phenotype only in homozygotes, alters the pro␣2(I) C-propeptide
The C-terminal propeptide (C-propeptide) of each chain folds into a structure that is stabilized by intra-chain disulfide bonds and exposes a chain selectivity domain [3] that directs the interaction of the correct three chains into trimers
Summary
Clinical Features of the Probands and Family Members—Patient 1 (P1) was identified at 39 years of age because of multiple fractures (Ͼ40), all of which occurred in adulthood He was 105 cm tall (ϽϽ5th centile), had normal scleral hue, and no evidence of dentinogenesis imperfecta. Patient 3 (P3) was a 33-year-old woman who presented with severe osteoporosis She had had at least 17 fractures, the first of which occurred at 8 years of age, mostly of the fingers, wrists, and toes. She was 162 cm tall (75th centile) with no alterations in scleral color, teeth, or hearing. X-rays showed thin diaphyses and funneled metaphyses and overall decreased bone density His teeth appeared somewhat translucent and his sclerae were white.
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