Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Exclusive paternal origin of new mutations in Apert syndrome

Abstract

Apert syndrome results from one or other of two specific nucleotide substitutions, both C→G transversions, in the fibroblast growth factor receptor 2 (FGFR2) gene. The frequency of new mutations, estimated as 1 per 65,000 live births, implies germline transversion rates at these two positions are currently the highest known in the human genome. Using a novel application of the amplification refractory mutation system (ARMS), we have determined the parental origin of the new mutation in 57 Apert families: in every case, the mutation arose from the father. This identifies the biological basis of the paternal age effect for new mutations previously suggested for this disorder.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Blank, C.E. Apert's syndrome (a type of acrocephalosyndactyly) — observations on a British series of thirty-nine cases. Ann. Hum. Genet. 24, 151–164 (1960).

    Article  CAS  PubMed  Google Scholar 

  2. Upton, J. & Zuker, R.M. Apert syndrome. Clin. Plast. Surg. 18, 1–435 (1991).

    Google Scholar 

  3. Slaney, S.F. et al. Differential effects of FGFR2 mutations on syndactyly and cleft palate in Apert syndrome. Am. J. Hum. Genet. 58, 923–932 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Cohen, M.M., et al. Birth prevalence study of the Apert syndrome. Am. J. Med. Genet. 42, 655–659 (1992).

    Article  PubMed  Google Scholar 

  5. Erickson, J.D. & Cohen, M.M. Jr. A study of parental age effects on the occurrence of fresh mutations for the Apert syndrome. Ann. Hum. Genet. 38, 89–96 (1974).

    Article  CAS  PubMed  Google Scholar 

  6. Lenz, W., Abhängigkeit der Mutationen vom Alter des Vaters. in Klinische Genetik in der Pädiatrie 2. Symposion in Mainz (eds. Spranger J. & olksdorf, M.) 125–136 (Stuttgart, Georg Thieme Vertag, 1980).

    Google Scholar 

  7. Risch, N., Reich, E.W., Wishnick, M.M. & McCarthy, J.G. Spontaneous mutation and parental age in humans. Am. J. Hum. Genet. 41, 218–248 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Vogel, F. & Motulsky, A.G., Human Genetics. Problems and Approaches (Springer-Verlag, Berlin, Heidelberg, 1986).

    Book  Google Scholar 

  9. Wilkie, A.O.M. et al. Apert syndrome results from localized mutations of GFR2 and is allelic with Crouzon syndrome. Nature Genet. 9, 165–172 (1995).

    Article  CAS  PubMed  Google Scholar 

  10. Park, W.-J. et al. Analysis of phenotypic features and FGFR2 mutations in Apert syndrome. Am. J. Hum. Genet. 57, 321–328 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Meyers, G.A. et al. FGFR2 exon IIIa and IIIc mutations in Crouzon, Jackson-Weiss, and Pfeiffer syndromes: evidence for missense changes, insertions, and a deletion due to alternative splicing. Am. J. Hum. Genet. 58, 491–498 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Sommer, S.S. Recent human germ-line mutation: inferences from patients with hemophilia B. Trends Genet. 11, 141–147 (1995).

    Article  CAS  PubMed  Google Scholar 

  13. Stamatoyannopoulos, G. & Nute, P.E. De novo mutations producing unstable Hbs or Hbs M. Hum. Genet. 60, 181–188 (1982).

    Article  CAS  PubMed  Google Scholar 

  14. Neel, J.V. et al. The rate with which spontaneous mutation alters the electrophoretic mobility of polypeptides. Proc. Natl. Acad. Sci. USA. 83, 389–393 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Wilkie, A.O.M., Morriss-Kay, G.M., Jones, E.Y. & Heath, J.K. Functions of fibroblast growth factors and their receptors. Curr. Biol. 5, 500–507 (1995).

    Article  CAS  PubMed  Google Scholar 

  16. Muenke, M. & Schell, U. Fibroblast-growth-factor receptor mutations in human skeletal disorders. Trends Genet. 11, 308–313 (1995).

    Article  CAS  PubMed  Google Scholar 

  17. Muenke, M. et al. A common mutation in the fibroblast growth factor receptor 1 gene in Pfeiffer syndrome. Nature Genet. 8, 269–274 (1994).

    Article  CAS  PubMed  Google Scholar 

  18. Carlson, K.M. et al. Parent-of-origin effects in multiple endocrine neoplasia Type 2B. Am. J. Hum. Genet. 55, 1076–1082 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Wilson, L.C., Oude Luttikhuis, M.E.M., Clayton, P.T., Fraser, W.D. & Trembath, R.C. Parental origin of GSα gene mutations in Albright's hereditary osteodystrophy. J. Med. Genet. 31, 835–839 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kitamura, Y., Scavarda, N., Wells, S.A. Jr. Jackson, C.E. & Goodfellow, R.J. Two maternally derived missense mutations in the tyrosine kinase domain of the RET protooncogene in a patient with de novo MEN 2B. Hum. Mol. Genet. 4, 1987–1988 (1995).

    Article  CAS  PubMed  Google Scholar 

  21. Newton, C.R. et al. Analysis of any point mutation in DNA. The amplification refractory mutation system (ARMS). Nucl. Acids Res. 17, 2503–2516 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kwok, S. et al. Effects of primer-template mismatches on the polymerase chain reaction: Human immunodeficiency virus type 1 model studies. Nucl. Acids Res. 18, 999–1005 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Shiang, R. et al. Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia. Cell. 78, 335–342 (1994).

    Article  CAS  PubMed  Google Scholar 

  24. Rousseau, F. et al. Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia. Nature. 371, 252–254 (1994).

    Article  CAS  PubMed  Google Scholar 

  25. Bellus, G.A. et al. Achondroplasia is defined by recurrent G380R mutations of FGFR3. Am. J. Hum. Genet. 56, 368–373 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Penrose, L.S. Parental age and mutation. Lancet. 2, 312–313 (1955).

    Article  Google Scholar 

  27. Orioli, I.M., Castilla, E.E., Scarano, G. & Mastroiacovo, P. Effect of paternal age in achondroplasia, thanatophoric dysplasia, and osteogenesis imperfecta. Am. J. Med. Genet. 59, 209–217 (1995).

    Article  CAS  PubMed  Google Scholar 

  28. Reiser, C.A., Pauli, R.M. & Hall, J.G. Achondroplasia: unexpected familial recurrence. Am. J. Med. Genet. 19, 245–250 (1984).

    Article  CAS  PubMed  Google Scholar 

  29. Dodinval, P. & Le Marec, B. Genetic counselling in unexpected familial recurrence of achondroplasia. Am. J. Med. Genet. 28, 949–954 (1987).

    Article  CAS  PubMed  Google Scholar 

  30. Meyers, G.A., Ortow, S.J., Munro, I.R., Przylepa, K.A. & Jabs, E.W. Fibroblast growth factor receptor 3 (FGFR3) transmembrane mutation in Crouzon syndrome with acanthosis nigricans. Nature Genet. 9, 462–464 (1995).

    Article  Google Scholar 

  31. Chandley, A.C. On the parental origin of de novo mutation in man. J. Med. Genet. 28, 217–223 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. White, P.C., Tusi-Luna, M.-T., New, M.I. & Speiser, R.W. Mutations in steroid 21 -hydroxylase (CYP21). Hum. Mutat. 3, 373–378 (1994).

    Article  CAS  PubMed  Google Scholar 

  33. Wolfe, K.H., Sharp, P.M. & Li, W.-H. Mutation rates differ among regions of the mammalian genome. Nature 337, 283–285 (1989).

    Article  CAS  PubMed  Google Scholar 

  34. Cooper, D.N. & Krawczak, M., Human Gene Mutation(BIOS Scientific Publishers Ltd., Oxford, 1993).

    Google Scholar 

  35. Driscoll, D.J. & Migeon, B.R. Sex difference in methylation of single-copy genes in human meiotic germ cells: implications for X chromosome inactivation, parental imprinting and origin of CpG mutations. Somatic. Cell Mol. Genet. 16, 267–282 (1990).

    Article  CAS  Google Scholar 

  36. Lichtenauer-Kaligis, E.G.R. et al. Genomic position influences spontaneous mutagenesis of an integrated retroviral vector containing the hprt cDNA as target for mutagenesis. Hum. Mol. Genet. 2, 173–182 (1993).

    Article  CAS  PubMed  Google Scholar 

  37. Ketterling, R.R., Vielhaber, E. & Sommer, S.S. The rates of G:C→T:A and G:C→C:G transversions at CpG dinucleotides in the human factor IX gene. Am. J. Hum. Genet. 54, 831–835 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Müller, B. et al. Estimation of the male and female mutation rates in Duchenne muscular dystrophy (DMD). Hum. Genet. 89, 204–206 (1992).

    Article  PubMed  Google Scholar 

  39. Ketterling, R.R. et al. Germ-line origins of mutation in families with hemophilia B: the sex ratio varies with the type of mutation. Am. J. Hum. Genet. 52, 152–166 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Richards, F.M. et al. Molecular analysis of de novo germline mutations in the von Hippel-Lindau disease gene. Hum. Mol. Genet. 4, 2139–2143 (1995).

    Article  CAS  PubMed  Google Scholar 

  41. Grimm, T. et al. On the origin of deletions and point mutations in Duchenne muscular dystrophy: most deletions arise in oogenesis and most point mutations result from events in spermatogenesis. J. Med. Genet. 31, 183–186 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Dryja, T.R. et al. Parental origin of mutations of the retinoblastoma gene. Nature. 339, 556–558 (1989).

    Article  CAS  PubMed  Google Scholar 

  43. Jadayel, D. et al. Paternal origin of new mutations in Von Recklinghausen neurofibromatosis. Nature 343, 558–559 (1990).

    Article  CAS  PubMed  Google Scholar 

  44. Stephens, K. et al. Preferential mutation of the neurofibromatosis type 1 gene in paternally derived chromosomes. Hum. Genet. 88, 279–282 (1992).

    Article  CAS  PubMed  Google Scholar 

  45. Rossiter, J.R. et al. Factor VIII gene inversions causing severe hemophilia A originate almost exclusively in male germ cells. Hum. Mol. Genet. 3, 1035–1039 (1994).

    Article  CAS  PubMed  Google Scholar 

  46. Antonarakis, S.E. et al. Factor VIII gene inversions in severe hemophilia A: results of an international consortium study. Blood. 96, 2206–2212 (1995).

    Google Scholar 

  47. li, S., Sobell, J.L., & Sommer, S.S., From molecular variant to disease: initial steps in evaluating the association of transthyretin M119 with disease. Am. J. Hum. Genet. 50, 29–41 (1992).

    CAS  Google Scholar 

  48. Allanson, J.E. Germinal mosaicism in Apert syndrome. Clin. Genet. 29, 429–433 (1986).

    Article  CAS  PubMed  Google Scholar 

  49. Byers, P.H., Wallis, G.A., & Willing, M.C., Osteogenesis imperfecta: translation of mutation to phenotype. J. Med. Genet. 28, 433–442 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Office of Population Censuses and Surveys. Registrar General's statistical review of England and Wales. Part II, Tables, population. (HMSO, London, 1964–1973).

  51. Office of Population Censuses and Surveys. Birth statistics, series FM1. HMSO, London, 1974–1993.

  52. Gyapay, G. et al. The 1993–94 Généthon human genetic linkage map. Nature Genet. 7, 246–339 (1994).

    Article  CAS  PubMed  Google Scholar 

  53. Bailey, D.M.D., Affara, N.A. & Ferguson-Smith, M.A. The X-Y homologous gene amelogenin maps to the short arms of both the X and Y chromosomes and is highly conserved in primates. Genomics 14, 203–205 (1992).

    Article  CAS  PubMed  Google Scholar 

  54. Miki, T. et al. Determination of ligand-binding specificity by alternative splicing: two distinct growth factor receptors encoded by a single gene. Proc. Natl. Acad. Sci. USA 89, 246–250 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Thein, S.L. & Hinton, J. A simple and rapid method of direct sequencing using Dynabeads. Br. J. Haemal. 79, 113–115 (1991).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Andrew O.M. Wilkie.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Moloney, D., Slaney, S., Oldridge, M. et al. Exclusive paternal origin of new mutations in Apert syndrome. Nat Genet 13, 48–53 (1996). https://doi.org/10.1038/ng0596-48

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng0596-48

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing