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:

Mutations in the fibrillin gene responsible for dominant ectopia lentis and neonatal Marfan syndrome

Nature Genetics volume 6, pages 64–69 (1994)Cite this article

Abstract

Mutations in the gene coding for fibrillin on chromosome 15 (FBN1) are known to cause Marfan syndrome (MFS). A related disorder, dominant ectopia lentis (EL), has also been linked genetically to this locus. We now describe ten novel mutations of FBN1 resulting in strikingly different phenotypes. In addition to classic MFS, FBN1 mutations also give rise to EL and a severe neonatal form of MFS. Interestingly, the neonatal MFS mutations are clustered in one particular region of FBN1, possibly providing new insights into genotype–phenotype comparisons.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Similar content being viewed by others

References

  1. Pyeritz, R.E. & McKusick, V.A. The Marfan syndrome: Diagnosis and management. New Engl. J. Med. 300, 772–777 (1979).

    Article  CAS  PubMed  Google Scholar 

  2. Kainulainen, K. Pulkkinen L., Savolainen, A., Kaitila, I. & Peltonen, L. Location on chromosome 15 of the gene defect causing Marfan syndrome. New Engl. J. Med. 323, 935–939 (1990).

    Article  CAS  PubMed  Google Scholar 

  3. Magenis, R.E., Maslen, C.L., Smith, L., Allen, L. & Sakai, L.Y. Localization of the fibrillin (FBN) gene to chromosome 15, band q21.1. Genomics 11, 346–351 (1991).

    Article  CAS  PubMed  Google Scholar 

  4. Dietz, H.C. et al. Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature 352, 337–339 (1991).

    Article  CAS  PubMed  Google Scholar 

  5. Kainulainen, K. et al. Two mutations in Marfan syndrome resulting in truncated fibrillin polypeptides. Proc. natn. Acad. Sci. U.S.A. 89, 5917–5921 (1992).

    Article  CAS  Google Scholar 

  6. Dietz, H.C. et al. Marfan phenotype variability in a family segregating a missense mutation in the epidermal growth factor-like motif of the fibrillin gene. J. clin. Invest. 89, 1674–1680 (1992).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Dietz, H.C., Saraiva, J.M., Pyeritz, R.E., Cutting, G.R. & Francomano, C.A. . Clustering of fibrillin (FBN1) missense mutations in Marfan syndrome patients at cysteine residues in EGF-like domains. Hum. Mut. 1, 366–374 (1992).

    Article  CAS  PubMed  Google Scholar 

  8. Dietz, H.C. et al. The skipping of constitutive exons in vivo induced by nonsense mutations. Science 259, 680–683 (1993).

    Article  CAS  PubMed  Google Scholar 

  9. Hewett, D.R., Lynch, J.R., Smith, R. & Sykes, B.C. A novel fibrillin mutation in the Marfan syndrome which could disrupt calcium binding of the epidermal growth factor-like module. Hum. molec. Genet. 2, 475–477 (1993).

    Article  CAS  PubMed  Google Scholar 

  10. Godfrey, M. et al. Prenatal diagnosis and a donor splice site mutation in fibrillin in a family with Marfan syndrome. Am. J. hum. Genet. 53, 472–480 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Tsipouras, P. et al. The international Marfan syndrome collaborative study: Genetic linkage of the Marfan syndrome, ectopia lentis, and congenital contractual arachnodactyly to the fibrillin genes on chromosomes 15 and 5. New Engl. J. Med. 326, 905–909 (1992).

    Article  CAS  PubMed  Google Scholar 

  12. Sakai, L.Y., Keene, D.R. & Engvall, E. Fibrillin, a new 350-kD glycoprotein is a component of extracellular microfibrils. J. cell Biol. 103, 2499–2509 (1986).

    Article  CAS  PubMed  Google Scholar 

  13. Maslen, C.L., Corson, G.M., Maddox, B.K., Glanville, R.W. & Sakai, L.Y. Partial sequence of a candidate gene for Marfan syndrome. Nature 352, 334–337 (1991).

    Article  CAS  PubMed  Google Scholar 

  14. Corson, G.M., Chalberg, S.C., Dietz, H.C., Sharbonneau, N.L. & Sakai, L.Y. Fibrillin binds calcium and is coded by cDNAs that reveal a multidomain 33. structure and alternatively spliced exons at the 5′ end. Genomics 17, 476–484 (1993).

    Article  CAS  PubMed  Google Scholar 

  15. Orita, M., Iwahana, H., Kanazava, H., Hayashi, K. & Sekiya, T. Detection of polymorphisms of human DNA by gel electrophoresis as single-strand conformation polymorphisms. Proc. natn. Acad. Sci. U.S.A. 86, 2766–2770 (1989).

    Article  CAS  Google Scholar 

  16. Orita, M., Suzuki, Y., Sekiya, T. & Hayashi, K. Rapid and sensitive detection of point mutations and DNA polymorphisms using the polymerase chain reaction. Genomics 5, 874–679 (1989).

    Article  CAS  PubMed  Google Scholar 

  17. Raghunath, M., Superti-Furga, A., Godfrey, M. & Steinmann, B. Decreased extracellular deposition of fibrillin and decorin in neonatal Marfan syndrome fibroblasts. Hum. Genet. 90, 511–515 (1993).

    Article  CAS  PubMed  Google Scholar 

  18. Buntinx, I.M. et al. Neonatal Marfan syndrome with congenital arachnodactyly, flexion contractures, and severe cardiac valve insufficiency. J. med. Genet. 28, 267–273 (1991).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Lee, B., Vitale, E., Superti-Furga, A., Steinmann, B. & Ramirez, F. G to T Transversion at position +5 of a splice donor site causes skipping of the preceding exon in the type III procollagen transcripts of a patient with Ehlers-Danlos syndrome type IV. J. biol. Chem. 266, 5256–5259 (1991).

    CAS  PubMed  Google Scholar 

  20. Lönnqvist, L. et al. A novel mutation of the fibrillin gene causing ectopia lentis. Genomics (in the press).

  21. Schollin, J., Bjarke, B. & Gustavson, K.-H. Probable homozygotic form of the Marfan syndrome in a newborn child. Acta. Pediatr. Scand. 77, 452–456 (1988).

    Article  CAS  Google Scholar 

  22. Hayashi, K. PCR-SSCP: a simple and sensitive method for detection of mutations in the genomic DNA. PCR Meth. Applic. 1, 34–38 (1991).

    Article  CAS  Google Scholar 

  23. Rees, D.J.G. et al. The role of β-hydroxyaspartate and adjacent carboxylate residues in the first EGF domain of human factor IX. EMBO J. 7, 2053–2061 (1988).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Komoriya, A. et al. Biologically active synthetic fragments of epidermal growth factor: Localization of a major receptor-binding region. Proc. natn. Acad. Sci. U.S.A. 81, 1351–1355 (1984).

    Article  CAS  Google Scholar 

  25. Appella, E. et al. The receptor-binding sequence of urokinase. J. biol. Chem. 262, 4437–1440 (1987).

    CAS  PubMed  Google Scholar 

  26. Handford, P.A. et al. Key residues involved in calcium-binding motifs in EGF-like domains. Nature 351, 164–167 (1991).

    Article  CAS  PubMed  Google Scholar 

  27. Winship, P.R. & Dragon, A.C. Identification of haemophilia B patients with mutations in the two calcium binding domains of factor IX: importance of a β-OH Asp 64->sn change. Br. J. Haematol. 77, 102–109 (1991).

    Article  CAS  PubMed  Google Scholar 

  28. Beighton, P. et al. International nosology of heritable disorders of connective tissue, Berlin, 1986. Am. J. med. Genet. 29, 581–594 (1988).

    Article  CAS  PubMed  Google Scholar 

  29. Kanzaki, T. et al. TGF-β1 binding protein: a component of the large latent complex of TGF-β1 with multiple repeat sequences. Cell 61, 1051–1061 (1990).

    Article  CAS  PubMed  Google Scholar 

  30. Byers, P.H. Osteogenesis imperfecta. In: Connective tissue and its heritable disorders: molecular, genetic, and medical aspects (eds Royce, P.M. & Steinmann, B.) 317–350 (Wiley-Liss, New York, 1993).

    Google Scholar 

  31. Beals, R.K. & Hecht, F. Congenital contractural arachnodactyly: A heritable disorder of connective tissue. J. Bone joint Surg. 53, 987–993 (1971).

    Article  CAS  PubMed  Google Scholar 

  32. Milewicz, D.M., Pyeritz, R.E., Crawford, E.S. & Byers, P.H. Marfan syndrome: defective synthesis, secretion, and extracellular matrix formation of fibrillin by cultured dermal fibroblasts. J. clin. Invest. 89, 79–86 (1992).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Mosher, D.F., Sottile, J., Wu, C. & McDonald, J.A. Assembly of extracellular matrix. Cell Biol. 4, 810–818 (1992).

    CAS  Google Scholar 

  34. Kelley, M.R., Kidd, S., Deutsch, W.A. & Young, M.W. Mutations altering the structure of epidermal growth factor-like coding sequences at the drosophila Notch locus. Cell 51, 539–548 (1987).

    Article  CAS  PubMed  Google Scholar 

  35. Sanger, F., Nicklen, S. & Coulson, A.R. DNA sequencing with chain-terminating inhibitors. Proc. natn. Acad. Sci. U.S.A. 74, 5463–5467 (1977).

    Article  CAS  Google Scholar 

  36. Casanova, J.-L., Pannetier, C., Jaulin, C. & Kourilsky, P. Optimal conditions for directly sequencing double-stranded PCR products with sequenase. Nucl. Acids Res. 18, 4028 (1990).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Syvänen, A.-C., Aalto-Setälä, K., Harju, L., Kontula, K. & Söderlund, H. A primer-guided nucleotide incorporation assay in the genotyping of apolipoprotein E. Genomics 8, 684–692 (1990).

    Article  PubMed  Google Scholar 

  38. Syvänen, A.-C. et al. Convenient and quantitative determination of the frequency of a mutant allele using solid-phase minisequencing: application to aspartylglucosaminuria in Finland. Genomics 12, 590–595 (1992).

    Article  PubMed  Google Scholar 

  39. Chou, P.Y. & Fasman, G.D. Prediction of β-turns. Biophys. J. 26, 367–384 (1979).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Human Molecular Genetics, National Public Health Institute, FIN-00300, Helsinki, Finland

    Katariina Kainulainen, Leena Karttunen, Lea Puhakka & Leena Peltonen

  2. Shriners Hospital for Crippled Children, Portland, 97201, Oregon, USA

    Lynn Sakai

Authors
  1. Katariina Kainulainen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Leena Karttunen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lea Puhakka
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lynn Sakai
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Leena Peltonen
    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

Kainulainen, K., Karttunen, L., Puhakka, L. et al. Mutations in the fibrillin gene responsible for dominant ectopia lentis and neonatal Marfan syndrome. Nat Genet 6, 64–69 (1994). https://doi.org/10.1038/ng0194-64

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng0194-64

This article is cited by

Search

Advanced 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