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A single amino acid deletion in the α2(I) chain of type I collagen produces osteogenesis imperfecta type III

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Abstract

RNase A protection analysis was used in the search for the cause of a non-lethal osteogenesis imperfecta (OI) phenotype (Sillence type III). Cleavage of the hybrid formed between a normal α2(I) sequence and RNA isolated from the patient indicated the presence of a mismatch. The position of the mismatch was determined and the corresponding area of COL1A2 was amplified using the polymerase chain reaction. Sequencing of cloned amplified DNA revealed the deletion, which was not present in either parent, of the final three bases of exon 19 in one of the patient's two COL1A2 alleles. The deletion results in the loss of amino acid 255 (a valine encoded by the last codon of exon 19) of the triple helical region of half of the α2(I) collagen chains but does not disrupt the splicing of the heterogeneous nuclear RNA (hnRNA). This provides further evidence that OI type III may result from autosomal dominant mutations rather than only from autosomal recessive mutations as had previously been believed.

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References

  • Armour JAL, Povey S, Jeremiah S, Jeffreys AJ (1990) Systematic cloning of human minisatellites from ordered array charomid libraries. Genomics 8:501–512

    Google Scholar 

  • Beighton P, Versfeld GA (1985) On the paradoxically high relative prevalence of osteogenesis imperfecta type III in the Black population of South Africa. Clin Genet 27:398–401

    Google Scholar 

  • Bonadio J, Byers PH (1985) Subtle structural alterations in the chains of type I procollagen produce osteogenesis imperfecta type II. Nature 316:363–366

    Google Scholar 

  • Bonadio J, Ramirez F, Barr M (1990) An intron mutation in the human α1(I) collagen gene alters the efficiency of pre-mRNA splicing and is associated with osteogenesis imperfecta type II. J Biol Chem 265:2262–2268

    Google Scholar 

  • Bouche JP (1981) The effect of spermidine on endonuclease inhibition by agarose contaminants. Anal Biochem 115:42–45

    Google Scholar 

  • Byers PH (1989) Inherited disorders of collagen gene structure and expression. Am J Med Genet 34:72–80

    Google Scholar 

  • Byers PH (1990) Brittle bones — fragile molecules: disorders of collagen gene structure and expression. Trends Genet 6:293–300

    Google Scholar 

  • Byers PH, Wallis GA, Willing MC (1991) Osteogenesis imperfecta: translation of mutation to phenotype. J Med Genet 28:433–442

    Google Scholar 

  • Chomczynski P, Sacchi N (1987) Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 162:156–159

    Article  CAS  PubMed  Google Scholar 

  • Church GM, Gilbert W (1984) Genomic sequencing. Proc Natl Acad Sci USA 81:1991–1995

    CAS  PubMed  Google Scholar 

  • Cohn DH, Starman BJ, Blumberg B, Byers PH (1990a) 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

    Google Scholar 

  • Cohn DH, Wallis G, Zhang X, Byers PH (1990b) Serine for glycine substitutions in the α1(I) chain of type I collagen: biological plasticity in the Gly-Pro-Hyp clamp at the carboxyl-terminal end of the triple helical domain. Matrix 10:236

    Google Scholar 

  • Crouse GF, Frischauf A, Lehrach H (1983) An integrated and simplified approach to cloning into plasmids and single-stranded phages. Method Enzymol 101:78–89

    Google Scholar 

  • Gibbs RA, Caskey CT (1987) Identification and localization of mutations at the Lesch-Nyhan locus by ribonuclease A cleavage. Science 236:303–305

    Google Scholar 

  • Hawkins JR, Dalgleish R (1991) The detection and mapping of point mutations by RNase A cleavage. In: Mathew CGP (ed) Methods in molecular biology vol 7: Molecular biology and medicine. Humana Press, Clifton, pp 111–121

    Google Scholar 

  • Hodges PE, Rosenberg LE (1989) The spf ash mouse: a missense mutation in the ornithine transcarbamylase gene also causes aberrant mRNA splicing. Proc Natl Acad Sci USA 86:4142–4146

    Google Scholar 

  • Jeffreys AJ, Neumann R, Wilson V (1990) Repeat unit sequence variation in minisatellites: a novel source of DNA polymorphism for studying variation and mutation by single molecule analysis. Cell 60:473–485

    Google Scholar 

  • Kawasaki ES, Wang AM (1989) Detection of gene expression. In: Erlich HA (ed) PCR technology: Principles and applications for DNA amplification. Stockton Press, New York

    Google Scholar 

  • Kogan SC, Doherty M, Gitschier J (1987) An improved method for prenatal diagnosis of genetic diseases by analysis of amplified DNA sequences. N Engl J Med 317:985–990

    Google Scholar 

  • Krawczak M, Cooper DN (1991) Gene deletions causing human genetic disease: mechanisms of mutagenesis and the role of the local DNA sequence environment. Hum Genet 86:425–441

    Google Scholar 

  • Kuivaniemi H, Sabol C, Tromp G, Sippola-Thiele M, Prockop DJ (1988a) A 19-base pair deletion in the pro-α2(I) gene of type I procollagen that causes in-frame RNA splicing from exon 10 to exon 12 in a proband with atypical osteogenesis imperfecta and his asymptomatic mother. J Biol Chem 263:11407–11413

    Google Scholar 

  • Kuivaniemi H, Tromp G, Chu M-L, Prockop DJ (1988b) Structure of a full-length cDNA clone for the preproα2(I) chain of human type I procollagen. Biochem J 252:633–640

    Google Scholar 

  • Kuivaniemi H, Tromp G, Prockop DJ (1991) Mutations in collagen genes: causes of rare and some common diseases in man. FASEB J 5:2052–2060

    Google Scholar 

  • Mead DA, Szczesna-Skorupa E, Kemper B (1986) Single-stranded DNA ‘blue’ T7 promoter plasmids: a versatile tandem promoter system for cloning and protein engineering. Protein Eng 1:67–74

    Google Scholar 

  • Miskulin M, Dalgleish R, Kluve-Beckerman B, Rennard SI, Tolstoshev P, Brantly M, Crystal RG (1986) Human type III collagen gene expression is coordinately modulated with the type I collagen genes during fibroblast growth. Biochemistry 25:1408–1413

    Google Scholar 

  • Murphy G, Ward ES (1989) Sequencing of double stranded DNA. In:Howe CJ, Ward ES (eds) Nucleic acid sequencing: a practical approach. IRL Press, Oxford, New York, Tokyo, pp 99–115

    Google Scholar 

  • Pack M, Constantinou CD, Kalia K, Neilsen KB, Prockop DJ (1989) Substitution of serine for α1(I)-glycine 844 in a severe variant of osteogenesis imperfecta minimally destabilises the triple helix of type I procollagen. J Biol Chem 264:19694–19699

    Google Scholar 

  • Pihlajaniemi T, Dickson LA, Pope FM, Korhonen VR, Nicholls A, Prockop DJ, Myers JC (1984) Osteogenesis imperfecta: cloning of a pro-α2(I) collagen gene with a frameshift mutation. J Biol Chem 259:12941–12944

    Google Scholar 

  • Pingoud A (1985) Spermidine increases the accuracy to type II restriction endonucleases. Eur J Biochem 147:105–109

    Google Scholar 

  • Prockop DJ (1990) Mutations that alter the primary structure of type I collagen. The perils of a system for generating large structures by the principle of nucleated growth. J Biol Chem 265:15349–15352

    Google Scholar 

  • Prockop DJ, Constantinou CD, Dombrowski KE, Hojima Y, Kadler KE, Kuivaniemi H, Tromp G, Vogel BE (1989) Type I procollagen: the gene-protein system that harbors most of the mutations causing osteogenesis imperfecta and probably more common heritable disorders of connective tissue. Am J Med Genet 34:60–67

    Google Scholar 

  • Pruchno CJ, Cohn DH, Wallis GA, Willing MC, Starman BJ, Zhang X, Byers PH (1991) Osteogenesis imperfecta due to recurrent point mutations at CpG dinucleotides in the COL1A1 gene of type I collagen. Hum Genet 87:33–40

    Google Scholar 

  • Sambrook J, Fritsch EF, Maniatis T (1989) Molecular cloning: a laboratory manual, 2nd edn. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY

    Google Scholar 

  • Scheffner M, Munger K, Byrne JC, Howley PM (1991) The state of the p53 and retinoblastoma genes in human cervical carcinoma cell lines. Proc Natl Acad Sci USA 88:5523–5527

    Google Scholar 

  • Shapiro MB, Senapathy P (1987) RNA splice junctions of different classes of eukaryotes: sequence statistics and functional implications in gene expression. Nucleic Acids Res 15:7155–7174

    CAS  PubMed  Google Scholar 

  • Short JM, Fernandez JM, Sorge JA, Huse WD (1988) λZap: a bacteriophage λ expression vector with in vivo excision properties. Nucleic Acids Res 16:7583–7600

    Google Scholar 

  • Sillence DO, Senn A, Danks DM (1979) Genetic heterogeneity in osteogenesis imperfecta. J Med Genet 16:101–116

    Google Scholar 

  • 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

    Google Scholar 

  • Starman BJ, Eyre D, Charbonneau H, Harrylock M, Weis MA, Weiss L, Graham JM, 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

    Google Scholar 

  • Talerico M, Berget SM (1990) Effect of 5′ splice site mutations on splicing of the preceding intron. Mol Cell Biol 10:6299–6305

    Google Scholar 

  • Tromp G, Prockop DJ (1988) Single base mutation in the proα2(I) collagen gene that causes efficient splicing of RNA from exon 27 to exon 29 and synthesis of a shortened but in frame proα2(I) chain. Proc Natl Acad Sci USA 85:5254–5258

    Google Scholar 

  • Viljoen D, Beighton P (1987) Osteogenesis imperfecta type III: an ancient mutation in Africa? Am J Med Genet 27:907–912

    Google Scholar 

  • Wallis GA, Starman BJ, Byers PH (1989) Clinical heterogeneity explained by molecular heterogeneity and somatic mosaicism. Am J Med Genet 45:A228

    Google Scholar 

  • 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 Med Genet 46:1034–1040

    Google Scholar 

  • Weil D, D'Alessio M, Ramirez F, de Wet W, Cole WG, Chan D, Bateman JF (1989a) A base substitution in the exon of a collagen gene causes alternative splicing and generates a structurally abnormal polypeptide in a patient with Ehlers-Danlos syndrome type VII. EMBOJ 8:1705–1710

    Google Scholar 

  • Weil D, D'Alessio M, Ramirez F, Steinmann B, Wirtz MK, Glanville RW, Hollister DW (1989b) Temperature-dependent expression of a collagen splicing defect in the fibroblasts of a patient with Ehlers-Danlos syndrome type VII. J Biol Chem 264:16804–16809

    Google Scholar 

  • 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

    Google Scholar 

  • Wenstrup RJ, Shrago-Howe AW, Lever LW, Phillips CL, Byers PH, Cohn DH (1991) The effects of different cysteine for glycine substitutions within α2(I) chains. J Biol Chem 266:2590–2594

    Google Scholar 

  • Willing MC, Cohn DH, Byers PH (1990) Frameshift mutation near the 3′ end of the COL1A1 gene of type I collagen predicts an elongated proα1(I) chain and results in osteogenesis imperfecta type I. J Clin Invest 85:282–290

    Google Scholar 

  • Winter E, Yamamoto F, Almoguera C, Perucho M (1985) A method to detect and characterise point mutations in transcribed genes: Amplification and overexpression of the mutant c-Ki-ras allele in human tumor cells. Proc Natl Acad Sci USA 82:7575–7579

    Google Scholar 

  • Wong Z, Wilson V, Patel I, Povey S, Jeffreys AJ (1987) Characterization of a panel of highly variable minisatellites cloned from human DNA. Ann Hum Genet 51:269–288

    Google Scholar 

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Authors and Affiliations

  1. Department of Genetics, University of Leicester, LE1 7RH, Leicester, UK

    Karen Molyneux & Raymond Dalgleish

  2. Departments of Pathology and Medicine, University of Washington, 98195, Seattle, WA, USA

    Barbra J. Starman & Peter H. Byers

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  1. Karen Molyneux
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  2. Barbra J. Starman
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  3. Peter H. Byers
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  4. Raymond Dalgleish
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Molyneux, K., Starman, B.J., Byers, P.H. et al. A single amino acid deletion in the α2(I) chain of type I collagen produces osteogenesis imperfecta type III. Hum Genet 90, 621–628 (1993). https://doi.org/10.1007/BF00202479

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  • DOI: https://doi.org/10.1007/BF00202479

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