Skip to main content
SpringerLink
Log in

Osteogenesis imperfecta due to recurrent point mutations at CpG dinucleotides in the COL1A1 gene of type I collagen

  • Original Investigations
  • Published:
Human Genetics Aims and scope Submit manuscript

Summary

Most individuals with osteogenesis imperfecta (OI) are heterozygous for dominant mutations in one of the genes that encode the chains of type I collagen. Each of the more than 30 mutations characterized to date has been unique to the affected member (s) of the family. We have determined that two individuals with a progressive deforming variety of OI, OI type III, have the same new dominant mutation [α1(I)gly154 to arg] and that two unrelated infants with perinatal lethal OI, OI type II, share a second new dominant muation [α1(I)gly1003 to ser]. These mutations occurred at CpG dinucleotides, in a manner consistent with deamination of a methylated cytosine residue, and raise the possibility that CpG dinucleotides are common sites of recurrent mutations in collagen genes. Further, these findings confirm that the OI type-III phenotype, previously thought to be inherited in an autosomal recessive manner, can result from new dominant mutations in the COL1A1 gene of type-I collagen.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Abadie V, Lyonnet S, Maurin N, Berthelon M, Caillaud C, Giraud F, Mattei JF, Rey F, Munnich A (1989) CpG dinucleotides are mutation hot spots in phenylketonuria. Genomics 5:936–939

    PubMed  Google Scholar 

  • Aitchison K, Ogilvie D, Honeyman M, Thompson E, Sykes B (1988) Homozygous osteogenesis imperfecta unlinked to collagen I genes. Hum Genet 78:233–236

    PubMed  Google Scholar 

  • Bateman JF, D Chan D, Walker ID, Rogers JG, Cole WG (1987) Lethal perinatal osteogenesis imperfecta due to substitution of agrinine for glycine at residue 391 of the α1(I) chains of type I collagen. J Biol Chem 262:7021–7027

    PubMed  Google Scholar 

  • Bateman JF, Lamande SR, Dahl HHM, Chan D, Cole WG (1988) Substitution of arginine for glycine 664 in the collagen α1(I) chain in lethal perinatal OI. J Biol Chem 263:11627–11630

    PubMed  Google Scholar 

  • Bernard MP, Chu ML, Myers JC, Ramirez F, Eikenberry EF, Prockop DJ (1983) Nucleotide sequences of complementary deoxyribonucleic acids for the proα1 chain of human type I procollagen. Statistical evaluation of structures that are conserved during evolution. 22:5213–5223

    Google Scholar 

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

    PubMed  Google Scholar 

  • Bonadio JF, Holbrook KA, Gelinas RE, Jacob J, and Byers PH (1985) Altered triple helical structure of tpye I procollagen in lethal perinatal osteogenesis imperfecta. J Biol Chem 260:1734–1742

    PubMed  Google Scholar 

  • Byers PH (1989) Disorders of collagen biosynthesis and structure. In: Scriver CS, Beaudet AL, Sly WS, Valle D (eds) Metabolic basis of inherited disease, 6th edn. McGraw-Hill, New York, pp 2805–2842

    Google Scholar 

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

    PubMed  Google Scholar 

  • Byers PH, Tsipouras P, Bonadio JF, Starman BJ, and 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

    PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  • Cooper DN, Youssoufian H (1988) The CpG dinucleotide and human genetic disease. Hum Genet 78:151–155

    PubMed  Google Scholar 

  • Coulondre C, Miller JH, Farabaugh PJ, Gilbert W (1978) Molecular basis of base substitution hotspots inEscherichia coli. Nature 274:775–780

    PubMed  Google Scholar 

  • D'Allessio M, Bernard M, Pretorius PJ, Wet W de, Ramirez F (1988) Complete nucleotide sequence of the region encompassing the first twenty-five exon of the human proα1(I) collagen gene (COL1A1). Gene 67:105–115

    PubMed  Google Scholar 

  • Davis LM, McGraw RA, Ware JL, Roberts HR, Stafford DW (1987) Factor IX Alabama: a point mutation in a clotting protein results in hemophilia B. Blood 69:140–143

    PubMed  Google Scholar 

  • Deak SB, Nicholls A, Pope FM, Prockop DJ (1983) The molecular defect in a non-lethal variant of osteogenesis imperfecta. Synthesis of proα2(1) chains wich are not incorporated into trimers of type I procollagen. J Biol Chem 258:15192–15197

    PubMed  Google Scholar 

  • Josse J, Kaiser AD, Kornberg A (1961) Enzymatic synthesis of deoxyribonucleic acid. VIII. Frequencies of nearest neighbor base sequences in deoxyribonucleic acid. J Biol Chem 236:864–875

    PubMed  Google Scholar 

  • Lathe R, (1985) Synthetic oligonucleotide probes deduced from amino acid sequence data: theoretical and practical considerations. J Mol Biol 183:1–12

    PubMed  Google Scholar 

  • Lindahl T (1979) DNA glycosylases, endonucleases for apurinic/ apyrimidinic sites, and base excision-repair. Prog Nucleic Acid Res Mol Biol 22:135–192

    PubMed  Google Scholar 

  • Maniatis T, Fritsch EF, Sambrook J (1982) Molecular cloning: a laboratory manual. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, pp 213–216

    Google Scholar 

  • Nicholls AC, Osse G, Schloon HG, Lenard HG, Deak S, Myers JC, Prockop DJ, Weigel WRF, Fryer P, Pope FM (1984) The clinical features of homozygous α2(I) collagen deficient osteogenesis imperfecta. J Med Genet 21:257–262

    PubMed  Google Scholar 

  • Pack M, Constantinou CD, Kalia K, Nielsen KB, Prockop DJ (1989) Substitution of serine for α1(I)-glycine 844 in a severe variant of osteogenesis imperfecta minimally destabilizes the triple helix of type I procollagen. The effects of glycine substitutions on thermal stability are either position or amino acid specific. J Biol Chem 264:19694–19699

    PubMed  Google Scholar 

  • Phillips CL, Shrago-Howe AW, Pinnell SR, Wenstrup RJ (1990) A substitution at a non-glycine position in the triple helical domain of proα2(I) collagen chains present in an individual with a variant of the Marfan syndrome. J Clin Invest 86:1723–1728

    PubMed  Google Scholar 

  • Pihlajaniemi T, Dickson LA, Pope FM, Korhonen VR, Nicholls AC, Prockop DJ, Myers JC (1984) Osteogenesis imperfecta: cloning of a proα2(I) collagen gene with a frameshift mutation. J Biol Chem 259:12941–12944

    PubMed  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

    PubMed  Google Scholar 

  • Puistola U, Turpeenniemi-Hujanen TM, Myllyla R, Kivirikko KI (1980) Studies on the lysyl hydroxylase reaction. II. Inhibition kinetics and the reaction mechanism. Biochem Biophys Acta 611:51

    PubMed  Google Scholar 

  • Saiki RK, Gelfand DH, Stoffel S, Scharf SJ, Higuchi R, Horn GT, Mullis KB, Erlich HA (1988) Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science 239:487–491

    PubMed  Google Scholar 

  • Sanger F, Nicklen S, Coulson AR (1977) DNA sequencing with chain-terminating inhibitors. Proc Natl Acid Sci USA 74:5463–5467

    Google Scholar 

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

    PubMed  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

    PubMed  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

    PubMed  Google Scholar 

  • Sykes B, Ogilvie D, Wordsworth P, Anderson J, Jones N (1986) Osteogenesis imperfecta is linked to both type I collagen structural genes. Lancet II:69–72

    Google Scholar 

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

    PubMed  Google Scholar 

  • Wallis GA, Starman BJ, Zinn AB, Byers PH (1990a) 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 Gent 46:1034–1040

    Google Scholar 

  • Wallis GA, Starman BJ, Schwartz MF, Byers PH (1990b) Substitution of arginine for glycine at position 847 in the triple helical domain of the α1(I) chain of type I collagen produces lethal osteogenesis imperfecta. Molecules that contain one or two abnormal chains differ in stability and secretion. J Biol Chem 265:18628–18633

    PubMed  Google Scholar 

  • Wenstrup RJ, Willing MC, Starman BJ, Byers PH (1990) Molecular basis of clinical heterogeneity in nonlethal variants of osteogenesis imperfecta: distinct biochemical phenotypes predict clinical severity. Am J Hum Genet 46:975–982

    PubMed  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

    PubMed  Google Scholar 

  • Wong C, Antonarakis SE, Goff SC, Orkin SH, Boehm CD, Kazazian HK (1986) On the origin and spread of β thalassemia recurrent observation of four mutations in different ethnic groups. Proc Natl Acad Sci USA 83:6529–6532

    PubMed  Google Scholar 

  • Youssoufian H, Kazazian HH, Phillips DG, Aronis S, Tsiftis G, Brown VA, Antonarakis SE (1986) Recurrent mutations in haemophilia A give evidence for CpG mutation hotspots. Nature 324:380–382

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departments of Medicine, Pediatrics and Pathology and the Center for Inherited Disease, University of Washington, 98195, Seattle, WA, USA

    Charles J. Pruchno, Gillian A. Wallis, Marcia C. Willing, Barbra J. Starman & Peter H. Byers

  2. Department of Pediatrics, University of California at Los Angeles, Los Angeles, CA, USA

    Daniel H. Cohn & Xiaoming Zhang

  3. Division of Medical Genetics, Cedar-Sinai Medical Center, 90048, Los Angeles, CA, USA

    Daniel H. Cohn & Xiaoming Zhang

Authors
  1. Charles J. Pruchno
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daniel H. Cohn
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gillian A. Wallis
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marcia C. Willing
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Barbra J. Starman
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xiaoming Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Peter H. Byers
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pruchno, C.J., Cohn, D.H., Wallis, G.A. et al. Osteogenesis imperfecta due to recurrent point mutations at CpG dinucleotides in the COL1A1 gene of type I collagen. Hum Genet 87, 33–40 (1991). https://doi.org/10.1007/BF01213088

Download citation

  • Received:

  • Revised:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01213088

Keywords

Search

Navigation