Summary
Four families presenting with familial osteogenesis imperfecta (OI) have been studied: 2 with the lethal type II and 2 with the severe type III form. Fibroblasts of the patients, all issue from non-consanguineous parents, produced normal and abnormal α(I) chains. These heterozygous mutations differentiate the recurrent forms from homozygous mutations characteristic of autosomal recessive forms. Although the identity of the mutations could not be determined, such recurrence of autosomal dominant OI is probably the result of germinal mosaicism in one of the parents. Biochemical results were consistent with a somatic mosaicism in the father's fibroblasts in one family. Moreover, our studies show that not only OI type II but also severe OI type III can arise from gonadal mosaicism. We discuss the importance of such a phenomenon for genetic counseling.
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Baldwin CT, Constantinou CD, Dumars KW, Prockop DJ (1989) A single base muation that converts glycine 907 of the α2(I) chain of type I procollagen to aspartate in a lethal variant of osteogenesis imperfecta. The single amino acid substitution near the carboxyl terminus destabilizes the whole triple helix. J Biol Chem 264:3002–3006
Barsh GS, Peterson KE, Byers PH (1981) Peptide mapping of collagen chains using CNBr cleavage of proteins within polyacrylamide gels. Collagen Rel Res 1:543–548
Bateman JF, Chan D, Mascara T, Rogers JG, Cole WG (1986) Collagen defects in lethal perinatal osteogenesis imperfecta. Biochem J 240:699–708
Bateman JF, Chan D, Walker ID, Rogers JG, Cole WG (1987) Lethal perinatal osteogenesis imperfecta due to the substitution of arginine for glycine at residue 391 of the α1(I) chain of type I collagen. J Biol Chem 262:7021–7027
Bateman JF, Lamande S, Dahl M, Chan D, Cole WG (1988) Substitution of arginine for glycine 664 in the collagen α1 (I) chain in lethal perinatal osteogenesis imperfecta: demonstration of the peptide defect by in vitro expression of the mutant cDNA. J Biol Chem 263:11627–11630
Bonaventure J, Cohen-Solal L, Lasselin C, Allain JC, Maroteaux P (1986) Abnormal procollagen synthesis in fibroblasts from three patients of the same family with a severe form of osteogenesis imperfecta (type III). Biochim Biophys Acta 889:23–34
Bonaventure J, Zylberberg L, Cohen-Solal L, Allain JC, Lasselin C, Maroteaux P (1989) A new lethal brittle bone syndrome with increased amount of type V collagen in a patient. Am J Hum Genet 33:299–310
Bruckner P, Prockop DJ (1981) Proteolytic enzymes as probes for the triple helical conformation of collagen. Anal Biochem 110:360–368
Byers PH, Tsipouras P, Bonadio JF, Starman BJ, Schwartz RC, (1988) Perinatal lethal osteogenesis imperfecta (OI type II): a biochemically heterogeneous disorder usually due to new mutations in the genes for type I collagen. Am J Hum Genet 42:237–248
Cohen-Solal L, Bonaventure J, Zylberberg L, Lasselin C, Maroteaux P (1988) Heterozygous mutation in two siblings with a lethal osteogenesis imperfecta: problem of inheritance. In: Glimcher MJ, Lian JB (eds) Proceedings of the Third International Conference on the Chemistry and Biology of Mineralized tissue, Chatham, Mass. Gordon & Breach, New York, p 823
Cohn DH, Byers PH, Steinmann B, Gelinas RE (1986) Lethal osteogenesis imperfecta resulting from a single nucleotide change in one human pro α1(I) collagen allele. Proc Natl Acad Sci USA 83:6045–6047
Cohn DH, Starman BJ, Blumberg B, Byers PH (1990) Recurrence of lethal osteogenesis imperfecta due to parental mosaicism for a dominant mutation in a human type I collagen gene (COL1A1). Am J Hum Genet 46:591–601
Cole WG, Chow CW, Rogers JG, Bateman JF (1990) The clinical features of three babies with osteogenesis imperfecta resulting from the substitution of glycine by arginine in the proα1(I) chain of type I procollagen. J Med Genet 27:228–235
Constantinou CD, Nielsen KB, Prockop DJ (1989) Lethal variant of osteogenesis imperfecta has a single base mutation that substitutes cysteine for glycine 904 of the α1(I) chain of type I procollagen. The asymptomatic mother has an unidentified mutation producing an overmodified and unstable type I procollagen. J Clin Invest 83:574–584
Constantinou CD, Pack M, Young SB, Prockop DJ (1990) Phenotypic heterogeneity of osteogenesis imperfecta: the mildly affected mother of a proband with a lethal variant has the same mutation substituting cysteine for α1-glycine 904 in a type I procollagen gene (COL1A1). Am J Hum Genet 47:670–679
Lamande SR, Dahl HHM, Cole WG, Bateman JF (1989) Characterization of point mutations in the collagen COL1A1 and COL1A2 genes causing lethal perinatal osteogenesis imperfecta. J Biol Chem 264:15809–15812
Maroteaux P, Frezal J, Cohen-Solal L, Bonaventure J (1986) Les formes anténatales de l'ostéogenese imparfaite. Arch Fr Pediatr 43:235–241
Neville DM, Glossmann H (1974) Molecular weight determination of membrane protein and glycoprotein subunits by discontinuous gel electrophoresis in dodecyl sulfate. Methods Enzymol 32B: 92–102
Sillence DO, Senn A, Danks DM (1979) Genetic heterogeneity in osteogenesis imperfecta. J Med Genet 16:101–106
Sillence DO, Barlow KK, Garbera P, Hall JG, Rimoin DL (1984) Osteogenesis imperfecta type II. Delineation of the phenotype with reference to genetic heterogeneity. Am J Med Genet 17:407–423
Sillence DO, Barlow KK, Cole WG, Dietrich S, Garber AP, Rimoin DL (1986) Osteogenesis imperfecta type III. Delineation of the phenotype with reference to genetic heterogeneity. Am J Med Genet 23:821–832
Starman BJ, Eyre D, Charbonneau H, Harrylock M, Weis MA, Weiss L, Graham JM Jr, Byers PH (1989) Osteogenesis imperfecta: the position of substitution for glycine by cysteine in the triple helical domain of the proα1(I) chains of type I collagen determines the clinical phenotype. J Clin Invest 84:1206–1214
Stegeman H, (1958) Mikrobestimmung von Hydroxyprolin mit Chloramin T und p. dimethylaminobenzaldehyd. Z Physiol Chem 311:41–45
Steinmann B, Rao VH, Vogel A, Bruckner P, Gitzelmann R, Byers PH (1984) Cystine in the triple-helical domain of one allelic product of the α1(I) gene of type I collagen produces a lehal form of osteogenesis imperfecta. J Biol Chem 259:11129–11138
Sykes B (1990) Bone disease cracks genetics. Nature 348:18–20
Thompson EM, Young ID, Hall CM, Pembrey ME (1987) Osteogenesis imperfecta type IIA: evidence for dominant inheritance. J Med Genet 24:386–389
Wallis GA, Starman BJ, Zinn AB, Byers PH (1990) Variable expression of osteogenesis imperfecta in a nuclear family is explained by somatic mosaicism for a lethal point mutation in the α1(I) gene (COL1A1) of type I collagen in a parent. Am J Hum Genet 46:1034–1040
Wenstrup RJ, Willing MC, Starman BJ, Byers PH (1990) Distinct biochemical phenotypes predict clinical severity in nonlethal variants of osteogenesis imperfecta. Am J Hum Genet 46:975–982
Wiestner MT, Krieg T, Horlein D, Glanville RW, Fietzek P, Muller PK (1979) Inhibiting effect of procollagen peptides on collagen synthesis in fibroblast cultures. J Biol Chem 254:7016–7023
Young JD, Harper PS (1980) Recurrence risk in osteogenesis imperfecta congenita. Lancet I:432
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Cohen-Solal, L., Bonaventure, J. & Maroteaux, P. Dominant mutations in familial lethal and severe osteogenesis imperfecta. Hum Genet 87, 297–301 (1991). https://doi.org/10.1007/BF00200907
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DOI: https://doi.org/10.1007/BF00200907