Skip to main content
SpringerLink
Log in

Review: The fragile X syndrome: Isolation of the FMR-1 gene and characterization of the fragile X mutation

  • Chromosoma Focus
  • Published:
Chromosoma Aims and scope Submit manuscript

Conclusion

Rapid progress has been made in the analysis of the fragile X syndrome during 1991. Different groups have discovered that fragile X chromosomes are preferentially methylated. In these X chromosomes an insertion has been found in the methylated region.

The FMR-1 gene, the transcription of which is shut off in patients, has been isolated. The expansion found in fragile X chromosomes is localized in the coding region of the FMR-1 gene. The fragile X syndrome results from mutations in a (CGG)n repeat found in the coding region of the FMR-1 gene. It will be crucial to determine the FMR-1 protein product in order to learn more about the function of the gene.

Diagnosis of the unstable region by DNA analysis is now available as an efficient and reliable test for the diagnosis of carriers, as well as for prenatal diagnosis.

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

  • Bell MV, Hirst MC, Nakahori Y, MacKinnon RN, Roche A, Flint TJ, Tommerup N, Tranebjaerg L, Froster-Iskenius U, Kerr B, Turner G, Lindebaum D, Winter R, Pembrey M, Thibodeau S, Davies KE (1991) Physical mapping across the fragile X: Hypermethylation and clinical expression of the fragile X syndrome. Cell 64:861–866

    Google Scholar 

  • Brown WT (1990) The fragile X: progress towards solving the puzzle. Am J Hum Genet 47:175–180

    Google Scholar 

  • Brown WT, Gross AC, Chan C, Jenkins EC (1985) Genetic linkage heterogeneity in the fragile X syndrome. Hum Genet 78:71:11–18

    Google Scholar 

  • Brown WT, Gross AC, Chan C, Jenkins EC, Mandel J-L, Oberlé I, Arveiler B, Novelli G, Thibodeau S, Hagerman R, Summers K, Turner G, White BN, Mulligan L, Forster-Gibson C, Holden JJA, Zoll B, Krawzak M, Gonnewardena P, Gustavson KH, Petterson U, Holmgren C, Schwartz C, Howard-Peebles PN, Murphy P, Breg WR, Veenema H, Carperter NJ (1988) Multilocus analysis of the fragile X syndrome. Hum Genet 78:201–205

    Google Scholar 

  • Camerino G, Mattei MG, Mattei JF, Jaye M, Mandel JL (1983) Close mapping of fragile X mental retardation syndrome to haemophilia B and transmission through a normal male. Nature 306:701–704

    Google Scholar 

  • Dahl N, Goonewardena P, Malmgren H, Gustavson KH, Holmgren G, Seemanowa E, Anneren G, Flood A, Pettersson U (1989) Linkage analysis of families with fragile X mental retardation using a novel RFLP marker (DXS304). Am J Hum Genet 45:304–309

    Google Scholar 

  • Djabali M, Nguyen C, Biunno I, Oostra BA, Mattei M-G, Ikeda J-E, Jordan BR (1991) Laser microdissection of the fragile X region: identification of cosmid clones and of conserved sequences in this region. Genomics 10:1053–1060

    Google Scholar 

  • Fish GS, Arinami T, Froster-Iskenius U, Fryns JP, Curfs LM, Borggraef M, Howard-Peebles PN, Schwartz CE, Simensen RJ, Shapiro LR (1991) Relationship between age and IQ among fragile X males: a multicenter study. Am J Med Genet 38:481–487

    Google Scholar 

  • Fu Y-H, Kuhl DPA, Pizzuti A, Pieretti M, Sutcliffe J, Richards S, Verkerk AJMH, Holden JJA, Fenwick RG, Warren ST, Oostra BA, Nelson DL, Caskey CT (1991) Variation of the CGG repeat at the fragile X site results in genetic instability: resolution of the Sherman paradox. Cell 67:1047–1058

    Google Scholar 

  • Gustavson KH, Blomquist H, Holmgren G (1986) Prevalence of fragile X syndrome in mentally retarded children in a Swedish county. Am J Hum Genet 23:581–588

    Google Scholar 

  • Heitz D, Rousseau F, Devys D, Saccone S, Abderrahim H, Le Paslier D, Cohen D, Vincent A, Toniolo D, Della Valle G, Johnson S, Schlessinger D, Oberlé I, Mandel JL (1991) Isolation of sequences that span the fragile X and identification of a fragile X-related CpG island. Science 251:1236–1239

    Google Scholar 

  • Hirst HC, Roche A, Flint TJ, Mackinnon RN, Bassett JHD, Nakahori Y, Watson JE, Bell MV, Patterson MN, Boyd Y, Thomas NST, Knight SJL, Warren ST, Hors-Cayla M, Schmidt M, Davies KE (1991a) Linear order of new established markers around the fragile site at Xq27.3. Genomics 10:243–249

    Google Scholar 

  • Hirst MC, Rack K, Makahori Y, Roche A, Bell MV, Flynn G, Christadoulou Z, Mackinnon RN, Francis M, Littler AJ, Anand R, Poustka A-M, Lehrach H, Schlessinger D, D'Urso M, Buckle VJ, Davies KE (1991b) A YAC contig across the fragile X site defines the region of fragility. Nucleic Acids Res 19:3283–3288

    Google Scholar 

  • Hirst MC, Knight S, Davies K, Cross G, Ocraft K, Raeburn S, Heeger S, Eunpu D, Jenkins EC, Lindenbaum R (1991c) Prenatal diagnosis of fragile X syndrome. Lancet 338:956–957

    Google Scholar 

  • Hulsebos ThJM, Oostra BA, Broersen S, van Oost BA, Westerved A (1991) New distal marker closely linked to the fragile X locus. Hum Genet 87:369–372

    Google Scholar 

  • Jacky PB, Ahuja YR, Anyane-Yeboa K, Breg WR, Carpenter NJ, Froster-Iskenius UG, Fryns JP, Glover TW, Gustavson KH, Hoegerman SF, Holmgren G, Howard-Peebles PN, Jenkins EC, Krawczun M, Neri G, Pettigrew A, Schaap T, Schonber SA, Shapiro LR, Spinner N, Steinbach P, Vianna-Morgante AM, Watson MS, Wilmot PL (1991) Guidelines for the preparation and analysis of the fragile X chromosome in lymphocytes. Am J Med Genet 38:400–403

    Google Scholar 

  • Jeffreys AJ, Roule NJ, Wilson V, Wong Z (1988) Spontaneous mutation rates to new length alleles at tandem-repetitive hypervariable loci in human DNA. Nature 332:278–281

    Google Scholar 

  • Kremer EJ, Yu S, Pritchard M, Nagaraja R, Heitz D, Lynch M, Baker E, Hyland VJ, Little RD, Wada M, Toniolo D, Vincent A, Rousseau F, Schlessinger D, Sutherland G, Richards RI (1991a) Isolation of a human DNA sequence which spans the fragile X. Am J Hum Genet 49:656–661

    Google Scholar 

  • Kremer EJ, Pritchard M, Lynch M, Yu S, Holman K, Baker E, Warren ST, Schlessinger D, Sutherland GR, Richards RI (1991b) Mapping of DNA instability at the fragile X to a trinucleotide repeat sequence p(CCG)n. Science 252:1711–1714

    Google Scholar 

  • Laird CD (1987) Proposed mechanism of inheritance and expression of the human fragile-X syndrome of mental retardation. Genetics 117:587–599

    Google Scholar 

  • Lubs HA (1969) A marker X-chromosome. Am J Hum Genet 21:231–244

    Google Scholar 

  • Mackinnon RN, Hirst MC, Bell MV, Watson JEV, Claussen U, Ludecke HJ, Senger G, Hortshemke B, Davies KE (1990) Microdissection of the fragile X region. Am J Hum Genet 47:181–187

    Google Scholar 

  • Martin JP, Bell J (1943) A pedigree of mental defect showing sexlinkage. J Neurol Psych 6:154–157

    Google Scholar 

  • Nielsen KB, Tommerup N, Poulsen H, Jacobsen P, Beck B, Mikkelsen M (1983) Carrier detection and X inactivation studies in the fragile X syndrome. Cytogenetic studies in 63 obligate and potential carriers of the fragile X. Hum Genet 64:240–245

    Google Scholar 

  • Oberlé I, Rousseau F, Heitz D, Kretz C, Devys D, Hanauer A, Boué J, Bertheas MF, Mandel JF (1991) Instability of a 550-base pair DNA segment and abnormal methylation in fragile X syndrome. Science 252:1097–1102

    Google Scholar 

  • Oostra BA, Hupkes PE, Perdon LF, van Bennekom CA, Bakker E, Halley DJJ, Schmidt M, Du Sart D, Smits A, Wieringa B, van Oost BA (1990) New polymorphic DNA marker close to the fragile site FRAXA. Genomics 6:129–132

    Google Scholar 

  • Opitz JM, Sutherland GR (1984) Conference report: International workshop on the fragile X and X-linked mental retardation. Am J Med Genet 17:5–94

    Google Scholar 

  • Pembrey ME, Winter RM, Davies KE (1985) A premutation that generates a defect at crossing over explains the inheritance of Fragile X mental retardation. Am J Med Genet 21:709–717

    Google Scholar 

  • Pieretti M, Zhang F, Fu Y-H, Warren ST, Oostra BA, Caskey CT, Nelson DL (1991) Absence of expression of the FMR-1 gene in fragile X syndrome. Cell 66:817–822

    Google Scholar 

  • Poustka A, Dietrich A, Langenstein G, Toniolo D, Warren ST, Lehrach H (1991) Physical map of human Xq27-qter: localizing the region of the fragile X mutation. Proc Natl Acad Sci USA 88:8302–8306

    Google Scholar 

  • Riggins GJ, Sherman SL, Oostra BA, Feitell D, Sutcliffe JS, Nelson DL, van Oost BA, Smits APT, Kuhl D, Caskey CT, Warren ST (1992) Characterization of a highly polymorphic dinucleotide repeat 150 kb proximal to the fragile site. Am J Med Genet, in press

  • Rousseau F, Vincent A, Rivella S, Heitz D, Tribioli C, Maestrini E, Warren ST, Suthers GK, Goodfellow P, Mandel JL, Toniolo D, Oberlé I (1991a) Four chromosomal breakpoints and four new probes mark out a 10cM region encompassing the FRAXA locus. Am J Hum Genet 48:108–116

    Google Scholar 

  • Rousseau F, Heitz D, Biancalana V, Blumenfeld S, Kretz C, Boué J, Tommerup N, van der Hagen C, DeLozier-Blanchet C, Croquette M-F, Gilgenkrantz S, Jalbert P, Voelckel M-A, Oberlé I, Mandel J-L (199b) Direct diagnosis by DNA analysis of the fragile X syndrome of mental retardation. New Engl J Med 325:1673–1681

    Google Scholar 

  • Sherman SL, Jacobs PA, Morton NE, Froster-Iskenius U, Howard-Peebles PN, Nielsen KB, Partington NW, Sutherland GR, Turner G, Watson M (1985) Further segregation of the fragile X syndrome with special reference to transmitting males. Hum Genet 69:3289–3299

    Google Scholar 

  • Sutherland GR (1977) Fragile sites on human chromosome: demonstration of their dependence on the type of tissue culture medium. Science 197:265–266

    Google Scholar 

  • Sutherland GR, Baker E (1986) Effects of nucleotides on expression of the folate sensitive fragile site. Am J Med Genet 23: 409–417

    Google Scholar 

  • Sutherland GR, Hecht F (1985) Fragile sites on human chromosomes. Oxford University Press, New York, pp 113–131

    Google Scholar 

  • Sutherland GR, Ledbetter DH (1989) Report of the committee on cytogenetic markers. Cytogenet Cell Genet 51:452–458

    Google Scholar 

  • Sutherland GR, Gedeon A, Kornman L, Donnelly A, Byard RW, Mulley JC, Kremer E, Lynch M, Pritchard M, Yu S, Richards RI (1991) Prenatal diagnosis of fragile X syndrome by direct detection of the unstable DNA sequence. N Engl J Med 325:1720–1722

    Google Scholar 

  • Suthers GK, Callen CF, Hyland VJ, Kozman HM, Baker E, Eyre H, Harper PS, Roberts SH, Hors-Cayla MC, Davies KE, Bell MV, Sutherland GR (1989) A new DNA marker tightly linked to the fragile X locus (FRAXA). Science 246:1298–1300

    Google Scholar 

  • Suthers GK, Mulley JC, Voelckel MA, Dahl N, Vaisanen ML, Steinbach P, Glass IA, Schwartz CE, van Oost BA, Thibodeau SN, Haites NE, Oostra BA, Schinzel A, Carballo M, Morris CP, Hopwood JJ, Sutherland GF (1991a) Linkage homogeneity near the fragile X locus in normal and fragile X families. Genomics 10:576–582

    Google Scholar 

  • Suthers GK, Mulley JC, Voeckel MA, Dahl N, Vaisanen ML, Steinbach P, Glass IA, Schwartz CE, van Oost BA, Thibodeau SN, Haites NE, Oostra BA, Giné R, Carballo M, Morris CP, Hopwood JJ, Sutherland GR (1991b) Genetic mapping of new DNA probes at Xq27 defines a strategy for DNA studies in the fragile X syndrome. Am J Hum Genet 48:460–467

    Google Scholar 

  • Verkerk AJMH, Pieretti M, Sutcliffe JS, Fu Y, Kuhl DPA, Pizzuti A, Reiner O, Richards S, Victoria MF, Zhang F, Eussen BE, van Ommen G-JB, Blonden LAJ, Riggins GJ, Chastain JL, Kunst CB, Galjaard H, Caskey CT, Nelson DL, Oostra BA, Warren ST (1991) Identification of a gene (FMR-1) containing a CGG repeat coincident with a fragile X breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell 65:905–914

    Google Scholar 

  • Verkerk AJHM, Eussen EHJ, van Hemel JO, Oostra BA (1992) The limited size of the fragile site shown by fluorescence in situ hybridization. Am J Med Genet (in press)

  • Vincent A, Heitz D, Petit C, Kretz C, Oberlé I, Mandel JF (1991) Abnormal pattern detected in fragile X patients by pulse-field gel electrophoresis. Nature 349:624–626

    Google Scholar 

  • Warren ST, Zhang F, Licamelli GR, Peters JF (1987) The fragile X site in somatic cell hybrids: an approach for molecular cloning of fragile sites. Science 237:420–423

    Google Scholar 

  • Webb TP, Bundey SE, Thake AI, Todd J (1986) Population incidence and segregation ratios in the Martin-Bell syndrome. Am J Med Genet 23:573–580

    Google Scholar 

  • Yu S, Pritchard M, Kremer E, Lynch M, Nancarrow J, Baker E, Holman K, Mulley JC, Warren ST, Schlessinger D, Sutherland GR, Richards RI (1991) Fragile X genotype characterized by an unstable region of DNA. Science 252:1179–1181

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Cell Biology, Erasmus University, P.O. Box 1738, NL-3000 DR, Rotterdam, The Netherlands

    Ben A. Oostra

  2. Department of Clinical Genetics, Erasmus University, P.O. Box 1738, NL-3000 DR, Rotterdam, The Netherlands

    Annemieke J. M. H. Verkerk

Authors
  1. Ben A. Oostra
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Annemieke J. M. H. Verkerk
    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

Oostra, B.A., Verkerk, A.J.M.H. Review: The fragile X syndrome: Isolation of the FMR-1 gene and characterization of the fragile X mutation. Chromosoma 101, 381–387 (1992). https://doi.org/10.1007/BF00582832

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00582832

Keywords

Search

Navigation