Advertisement

European Journal of Pediatrics

, Volume 154, Issue 2, pp 123–129 | Cite as

Genetic counselling on brittle grounds: Recurring osteogenesis imperfecta due to parental mosaicism for a dominant mutation

  • Michael Raghunath
  • Katrina Mackay
  • Raymond Dalgleish
  • Beat Steinmann
Medical Genetics Original Paper

Abstract

Osteogenesis imperfecta (OI), a dominantly inherited connective tissue disorder, is usually caused by defects in collagen I. There is growing evidence for parental mosaicism that results in affected children born to unaffected parents. This situation poses a difficult task for the geneticist because a mosaic parent may appear clinically healthy while carrying the mutation in a fraction of her or his gonadal cells. To illustrate this problem, we report a Swiss couple whose first child was affected with severe OI. The unexpected recurrence of the disorder in the second child raised the suspicion of a recessive trait or, rather, of parental mosaicism. We identified the responsible collagen mutation in the COL1A2 gene (Gly688Ser in the α2(I)-chain) in both children and demonstrated the father to be a somatic mosaic for this mutation and to have subtle clinical signs such as soft skin and short stature that may be a result of his mosaic state.

Key words

Osteogenesis imperfecta Collagen I Mosaicism Genetics Recurrence risk 

Abbreviations

OI

osteogenesis imperfecta

PCR

polymerase chain reaction

SSCP

single strand conformation polymorphism

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Abuelo DN, Byers PH (1991) Germline mosaicism in progressive deforming osteogenesis imperfecta (abstract). Am J Hum Genet 49: 125Google Scholar
  2. 2.
    Bonaventure J, Cohen-Solal L, Lasselin C, Maroteaux P (1992) A dominant mutation in the COL1A1 gene that substitutes glycine for valine causes recurrent lethal osteogenesis imperfecta. Hum Genet 89: 640–646CrossRefPubMedGoogle Scholar
  3. 3.
    Byers PH (1993) Osteogenesis imperfecta. In: Royce PM, Steinmann B (eds) Connective tissue and its heritable disorders: molecular, genetic, and medical aspects. Wiley-Liss, New York, pp 317–350Google Scholar
  4. 4.
    Byers PH, Tsipouras P, Bonadio JF, Starman BJ, Schwartz RC (1988) Perinatal lethal osteogenesis imperfecta (OI type II): a biochemically heterogenous disorder usually due to new mutations in the genes for type I collagen. Am J Hum Genet 42: 237–248PubMedGoogle Scholar
  5. 5.
    Cohen-Solal L, Bonaventure J, Maroteaux P (1991) Dominant mutations in familial lethal and severe osteogenesis imperfecta. Hum Genet 87: 297–301CrossRefPubMedGoogle Scholar
  6. 6.
    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: 591–601PubMedGoogle Scholar
  7. 7.
    Constantinou CD, Pack M, Young SB, Prockop DJ (1990) Phenotypic heterogeneity in 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 (COL1A1). Am J Hum Genet 47: 670–679PubMedGoogle Scholar
  8. 8.
    Constaninou-Deltas CD, Ladda RL, Prockop DJ (1993) Somatic cell mosaicism: another source of phenotypic heterogeneity in nuclear families with osteogenesis imperfecta. Am J Med Genet 45: 246–251CrossRefPubMedGoogle Scholar
  9. 9.
    Edwards MF, Wenstrup RJ, Byers PH, Cohn DH (1992) Recurrence of lethal osteogenesis imperfecta due to parental mosaicism for a mutation in the COL1A2 gene of type I collagen. The mosaic parent exhibits phenotypic features of a mild form of the disease. Human Mutation 1: 47–54CrossRefPubMedGoogle Scholar
  10. 10.
    Hall JG (1988) Somatic mosaicism: observations related to clinical genetics. Am J Hum Genet 43: 355–363PubMedGoogle Scholar
  11. 11.
    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, pp 89–97Google Scholar
  12. 12.
    Kogan SC, Doherty M, Gitschier J (1987) An improved method for prenatal diagnosis of genetic diseases by analysis of amplified sequences. N Engl J Med 317: 985–990PubMedGoogle Scholar
  13. 13.
    Mackay K, Byers PH, Dalgleish R (1993) An RT-PCR-SSCP screening strategy for detection of mutations in the gene encoding the α1 chain of type I collagen: application to four patients with osteogenesis imperfecta. Hum Mol Genet 2: 1155–1160PubMedGoogle Scholar
  14. 14.
    Marini JC, Lewis MB, Wang Q, Chen KJ, Orrison BM (1993) Serine for glycine substitutions in type I collagen in two cases of type IV osteogenesis imperfecta (OI). J Biol Chem 268: 2667–2673PubMedGoogle Scholar
  15. 15.
    Mottes M, Lira MMG, Valli M, Scarano G, Lonarda F, Forlino A, Cetta G, Pignatti PF (1993) Paternal mosaicism for a COL1A1 dominant mutation (α1 Scr-415) causes recurrent osteogenesis imperfecta. Human Mutation 2: 196–204CrossRefPubMedGoogle Scholar
  16. 16.
    Raghunath M, Steinmann B, DeLozier-Blanchet C, Extermann P, Superti-Furga A (1994) Prenatal diagnosis of collagen disorders by direct biochemical analysis of chorion villus biopsies. Pediatr Res 36: 441–448PubMedGoogle Scholar
  17. 17.
    Sambrook J, Fritsch EF, Maniatis T (1989) Molecular cloning: a laboratory manual, 2nd edn. Cold Spring Harbor, New YorkGoogle Scholar
  18. 18.
    Short JM, Fernandez JM, Sorge JA, Huse WD (1988) λ ZAP: a bacteriophage λ expression vector with in vivo excision properties. Nucl Acids Res 16: 7583–7600PubMedGoogle Scholar
  19. 19.
    Sillence DO, Senn A, Danks DM (1979) Genetic heterogeneity in osteogenesis imperfecta. J Med Genet 16: 101–116PubMedGoogle Scholar
  20. 20.
    Steinmann B, Rao VH, Vogel A, Bruckner P, Gitzelmann R, Byers PH (1984) Cysteine in the triple-helical domain of one allelic product of the α1(I) gene of type I collagen produces a lethal form of osteogenesis imperfecta. J Biol Chem 259: 11129–11138PubMedGoogle Scholar
  21. 21.
    Superti-Furga A, Steinmann B (1988) Impaired secretion of type III procollagen in Ehlers-Danlos syndrome type IV fibroblasts: correction of the defect by incubation at low temperature and demonstration of subtle structural alterations in the triple-helical region of the molecule. Biochem Biophys Res Comm 150: 140–147CrossRefPubMedGoogle Scholar
  22. 22.
    Thompson EM, Young ID, Hall CM, Pembrey ME (1987) Recurrence risks and prognosis in severe sporadic osteogenesis imperfecta. J Med Genet 24: 390–405PubMedGoogle Scholar
  23. 23.
    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: 1034–1040PubMedGoogle Scholar
  24. 24.
    Wallis GA, Sykes B, Byers PH, Mathew CG, Viljoen D, Beighton P (1993) Osteogenesis imperfecta type III: mutations in the type I collagen structural genes, COL1A1 and COL1A2, are not necessarily responsible. J Med Genet 30: 492–496PubMedGoogle Scholar
  25. 25.
    Wordsworth BP, Allsopp CEM, Young RP, Bell JI (1990) HLA-DR typing using DNA amplification by the polymerase chain reaction and sequential hybridization to sequence-specific oligonucleotide probes. Immunogenetics 32: 413–418CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 1995

Authors and Affiliations

  • Michael Raghunath
    • 1
  • Katrina Mackay
    • 2
  • Raymond Dalgleish
    • 2
  • Beat Steinmann
    • 1
  1. 1.Division of Metabolism, Department of PaediatricsUniversity of ZürichZürichSwitzerland
  2. 2.Department of GeneticsUniversity of LeicesterLeicesterUK

Personalised recommendations