Molecular Findings In Brazilian Patients With Osteogenesis Imperfecta

Osteogenesis imperfecta (OI) is a genetic disorder of increased bone fragility and low bone mass. Severity varies widely, ranging from intrauterine fractures and perinatal lethality to very mild forms without fractures. Most patients with a clinical diagnosis of OI have a mutation in the COL1A1 or COL1A2 genes that encode the chains of type I procollagen, the major protein in bones. Hence, the aim of the present study was to identify mutations in the COL1A1 gene in 13 unrelated Brazilian OI patients. This is the first molecular study of OI in Brazil. We found 6 mutations, 4 of them novel (c.1885delG, p.P239A, p.G592S, p.G649D) and 2 previously described (p.R237X and p.G382S). Thus, the findings show that there are no prevalent mutations in our sample, and that their distribution is similar to that reported by other authors, with preponderance of substitutions for glycine in the triple helix domain, causing OI types II, III and IV.461105108Berg, R.A., Prockop, D.J., The thermal transition of a non-hydroxylated form of collagen. Evidence for a role for hydroxyproline in stabilizing the triple-helix of collagen (1973) Biochem Biophys Res Commun, 52, pp. 115-220Byers, P.H., Brittle bones - Fragile molecules: Disorders of collagen gene structure and expression (1990) Trends Genet, 6, pp. 293-300Culbert, A.A., Wallis, G.A., Kadler, K.E., Tracing the pathway between mutation and the phenotype in Osteogenesis Imperfecta: Isolation of mineralization-Specific Genes (1996) Am J Med Genet, 63, pp. 167-174Dalgleish, R., The human type I collagen mutation database (1997) Nucleic Acids Res, 25, pp. 181-187Gajko-Galicka, A., Mutations in type I collagen genes resulting in osteogenesis imperfecta in human (2002) Acta Biochim Polon, 49, pp. 433-441Körkkö, J., Ala-Kokko, L., De Paeppe, A., Nuytinck, L., Barley, J., Prockop, D.J., Analysis of the COL1A1 and COL1A2 genes by PCR amplification and scanning by conformation-sensitive gel electrophoresis identifies only COL1A1 mutations in 15 patients with osteogenesis imperfecta type I: Identification of common sequences of null-allele mutations (1998) Am J Hum Genet, 62, pp. 98-110Mackay, K., Byers, P.H., Dalgleish, R., An RT-PCR-SSCP screening strategy for detection of mutations in the gene encoding the alpha 1 chain of type I collagen: Application to four patients with osteogenesis imperfecta (1993) Hum Mol Genet, 2, pp. 1155-1160Redford-Badwal, D.A., Stover, M.L., Valli, M., Mckinstry, M.B., Rowe, D.W., Nuclear retention of COL1A1 messenger RNA identifies null alleles causing mild Osteogenesis Imperfecta (1996) J Clin Invest, 97, pp. 1035-1040Sillence, D.O., Horton, W.A., Rimoin, D.L., Morphologic studies in the skeletal dysplasia (1979) Am J Path, 96, p. 813Spotila, L.D., Colige, A., Sereda, L., Constantinou-Deltas, C.D., Whyte, M.P., Riggs, B.L., Mutation analysis of coding sequences for type I procollagen in individuals with low Bone Density (1994) J Bone Miner Res, 9, pp. 923-932Willing, M.C., Deschenes, S.P., Slayton, R.L., Roberts, E.J., Premature chain termination is a unifying mechanism for COL1A1 null alleles in osteogenesis imperfecta type I cell strains (1996) Am J Hum Genet, 59, pp. 799-809Zhuang, J., Tromp, G., Kuivaniemi, H., Castells, S., Prockop, D.J., Substitution of arginine for glycine at position 154 of the alpha 1 chain of type I collagen in a variant of osteogenesis imperfecta: Comparison to previous cases with the same mutation (1996) Am J Med Genet, 61 (2), pp. 111-11