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Fragile×expression and×inactivation

I. The expression of the fragile site at Xq27.3 is not suppressed on inactive×chromosomes separated from the active homologue

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Summary

The inactive fragile×chromosomes of a 47,fra(X),fra(X),Y male with a typical fragile×phenotype were successfully separated from the active homologues by means of somatic cell hybridization. It was shown by FUdR-induction and caffein-posttreatment that the separated inactive×chromosomes expressed their fragile sites and that the presence of an active mutated \sxchromosome was not a prerequisite for fragile X expression. The fragility seems to be an intrinsic property of the individual fragile site. This result is in favour of the classical concept that the fragile site at Xq27.3 has a primary pathogenetic function in this syndrome, although the fragility itself could represent a secondary phenomenon related to an unknown alteration of the DNA in this chromosome region. It is also concluded that inactivation of the fragile\sxchromosome in females is not responsible for either false negative fragile\sxfindings or the observation of fragile\sxnegative colonies isolated from fragile\sxpositive fibroblasts in heterozygotes.

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References

  • Aldridge J, Kunkel L, Bruns G, Tantravahi U, LaLande M, Brewster T, Moreau E, Wilson M, Bromley W, Roderick T, Latt SA (1984) A strategy to reveal high frequency RFLPs along the human×chromosome. Am J Hum Genet 36:546–564

    Google Scholar 

  • Anson DS, Choo KH, Rees DJG, Gianelli F, Gould K, Huddleston JA, Brownlee GG (1984) The gene structure of the human antihaemophilic factor IX. EMBO J 3:1053–1060

    Google Scholar 

  • Barbi G, Steinbach P, Wiedenmann A, Vogel W (1984) Manifestation of the fragile site Xq27 in fibroblasts. III. A method to demonstrate R-type replication patterns and the fragile site. Hum Genet 65:76–78

    Google Scholar 

  • Barbi G, Steinbach P, Baur S, Vogel W (1985) Manifestation of the fragile site Xq27 in fibroblasts. IV. Clones from a heterozygous female do not manifest this site homogeneously on either the early or the late replicating×chromosome. Hum Genet 69:106–108

    Google Scholar 

  • Boyd Y, Fraser NJ (1990) Methylation patterns at the hypervariable locus DXS255 (M27β): correlation with X-inactivation status. Genomics (in press)

  • Boyd Y, Fraser NJ, Craig IW (1988) Specific methylation at the hypervariable DXS255 locus on the active X chromosomes: a simple system for the assessment of×inactivation status. J Med Genet 25:645

    Google Scholar 

  • Brown WT (1989) DNA studies of the fragile×mutation. In: KE Davies (ed) The fragile×syndrome. Oxford University Press, Oxford New York Tokyo, pp 76–101

    Google Scholar 

  • Brown WT, Cross A, Chan C, Jenkins EC, Mandel JL, 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, Krawczak M, Goonewardena P, Gustavson KH, Pettersson U, Holmgren G, Schwartz C, Howard-Peebles PN, Murphy P, Breg WR, Veenema H, Carpenter NJ (1988) Multilocus analysis of the fragile X syndrome. Hum Genet 78:201–205

    Google Scholar 

  • Connor JM, Pirrit LA, Yares JRW, Crossley JA, Imrie SJ, Colgan JM (1987) Linkage analysis using multiple Xq DNA polymorphisms in normal families, families with the fragile×syndrome, and other families with×linked conditions. J Med Genet 24:14–22

    Google Scholar 

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

    Google Scholar 

  • Daker MG, Chidiac P, Fear CN, Berry AC (1981) Fragile×in a normal male: A cautionary tale. Lancet 1:780

    Google Scholar 

  • Davies KE, Pearson PL, Harper PS, Murray JM, O'Brien T, Sarfarazi M, Williamson R (1983) Linkage analysis of two cloned DNA sequences flanking the Duchenne muscular dystrophy locus on the short arm of the human X-chromosome. Nucleic Acids Res 8:2303–2312

    Google Scholar 

  • Davies LG, Dibner MD, Battey JF (1986) Basic methods in molecular biology. Elsevier, New York Amsterdam London

    Google Scholar 

  • Dorkins H, Junien C, Mandel JL, Wrogemann K, Moison JP, Martinez M, Old JM, Bundey S, Schwartz M, Carpenter N, Hill D, Lindlof M, Chapelle A de la, Pearson PL, Davies KE (1985) Segregation analysis of a marker localized Xp21.2-p21.3 in Duchenne and Becker muscular dystrophy families. Hum Genet 71:103–107

    Google Scholar 

  • Fonatsch C (1983) Fragile×chromosome in fibroblasts: longitudinal study on technical variations. Clin Genet 23:229

    Google Scholar 

  • Fraser NJ, Boyd Y, Brownlee GG, Craig IW (1987) Multi-allelic RFLP for M27β, an anonymous single copy genomic clone at Xp11.3-Xcen [DXS255]. Nucleic Acids Res 15:9616

    Google Scholar 

  • Fraser NJ, Boyd Y, Craig IW (1989) Isolation and characterization of a human variable copy number tandem repeat at Xcenp-11.22. Genomics 5:144–148

    Google Scholar 

  • Froster-Iskenius U, Schulze A, Schwinger E (1984) Transmission of the marker×trait by unaffected males: conclusions from studies of large families. Hum Genet 67:419–427

    Google Scholar 

  • Fryns JP (1984) The fragile×chromosome. A study of 83 families. Clin Genet 26:497–528

    Google Scholar 

  • Fryns JP, Kleczkowska A, Wolfs I, Berghe H van den (1984) Klinefelter syndrome and two fragile×chromosomes. Clin Genet 26:445–447

    Google Scholar 

  • Hofker MH, Wapenaar MC, Goor N, Bakker E, Ommen GJB van, Pearson PL (1985) Isolation of probes detecting restriction fragment length polymorphisms from X-chromosome specific libraries: potential use for diagnosis of Duchenne muscular dystrophy. Hum Genet 70:148–156

    Google Scholar 

  • Hupkes PE, Bennekom CA van, Oost BA van, Oastra BA (1990) RN1, a new polymorphic marker near the fragile×locus (HGM10 assignment DXS369). Nucleic Acids Res 18:692

    Google Scholar 

  • Israel MH (1987) Autosomal suppressor gene for fragile-X: an hypothesis. Am J Med Genet 26:19–31

    Google Scholar 

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

  • Jennings M, Hall JG, Hoehn H (1980) Significance of phenotypic and chromosomal abnormalities in X-linked mental reatardation (Martin-Bell or Renpenning syndrome). Am J Med Genet 7:417–432

    Google Scholar 

  • Jolly DJ, Esty AC, Bernard HU, Friedmann T (1982) Isolation of a genomic clone partially encoding human hypoxanthine phosphoribosyltransferase. Proc Natl Acad Sci USA 79:5038–5041

    Google Scholar 

  • Kennerknecht I, Barbi G, Dahl N, Steinbach P (1991) How can the frequency of false negative findings in prenatal diagnoses of fra(X) be reduced? Experience with first trimester chorionic villi sampling. Am J Med Genet (in press)

  • Kunkel LM, Monaco AP, Middlesworth W, Ochs HD, Latt SA (1985) Specific cloning of DNA fragments absent from the DNA of a male patient with an X-chromosome deletion. Proc Natl Acad Sci USA 82:4778–4782

    Google Scholar 

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

    Google Scholar 

  • Laird CD (1988) Fragile-X mutation proposed to block complete reactivation in females of an inactive×chromosome. Am J Med Genet 30:693–696

    Google Scholar 

  • Ledbetter DH, Ledbetter SA, Nussbaum RL (1986) Implications of fragile×expression in normal males for the nature of the mutation. Nature 324:161–163

    Google Scholar 

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

    Google Scholar 

  • Martin JB, Bell J (1943) A pedigree of mental defect showing sex linkage. J Neurol Psychiatry 6:154–157

    Google Scholar 

  • Mulley JC, Sutherland GR (1987) Fragile×transmission and the determination of carrier probabilities for genetic counselling. Am J Med Genet 26:987–990

    Google Scholar 

  • Nussbaum RL, Ledbetter DH (1986) Fragile×syndrome: a unique mutation in man. Annu Rev Genet 20:109–145

    Google Scholar 

  • Nussbaum RL, Airhart SD, Ledbetter DH (1986a) A rodenthuman hybrid containing Xq24-qter translocated to a hamster chromosome expresses the Xq27 folate-sensitive fragile site. Am J Med Genet 23:457–466

    Google Scholar 

  • Nussbaum RL, Airhart SD, Ledbetter DH (1986b) Recombination and amplification of pyrimidine-rich sequences may be responsible for initiation and progression of the Xq27 fragile site: an hypothesis. Am J Med Genet 23:715–722

    Google Scholar 

  • Oberlé I, Drayna D, Camerino G, White R, Mandel JL (1985) The telomeric region of the human×chromosome long arm: presence of a highly polymorphic DNA marker and analysis of recombination frequency. Proc Natl Acad Sci USA 82:2824–2828

    Google Scholar 

  • Painter RB, Young BR (1980) Radiosensitivity in ataxia-telangiectasia: a new explanation. Proc Natl Acad Sci USA 77:7315–7317

    CAS  PubMed  Google Scholar 

  • Pembrey ME, Winter RM, Davies KE (1984) A premutation that generates the definite mutation by recombination explains the inheritance of the Martin Bell syndrome (fragile X). J Med Genet 21:299

    Google Scholar 

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

    Google Scholar 

  • Shapiro LR, Wilmot PL, Murphy PD, Breg WG (1988) Experience with multiple approaches to the prenatal diagnosis of the fragile×syndrome: Amniotic fluid, chorionic vilii, fetal blood and molecular methods. Am J Med Genet 30:347–354

    Google Scholar 

  • Sherman SL, Morton NE, Jacobs PA, Turner G (1984) The marker (X) syndrome: a cytogenetic and genetic analysis. Ann Hum Genet 48:21–37

    Google Scholar 

  • Sherman SL, Jacobs PA, Morton NE, Froster-Iskenius U, Howard-Peebles PN, Nielsen KB, Partington MW, Sutherland GR, Turner G, Watson M (1985) Further segregation analysis of the fragile (X) syndrome with special reference to transmitting males. Hum Genet 69:289–299

    Google Scholar 

  • Sherman SL, Rogatko A, Turner G (1988) Recurrence risks for relatives in families with an isolated case of the fragile×syndrome. Am J Med Genet 31:754–765

    Google Scholar 

  • Southern E (1975) Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol 98:503–517

    CAS  PubMed  Google Scholar 

  • Steinbach P (1986) Mental impairment in Martin-Bell syndrome is probably determined by interaction of several genes: Simple explanation of phenotypic differences between unaffected and affected males with the same×chromosome. Hum Genet 72:248–252

    Google Scholar 

  • Steinbach P, Barbi G, Baur S, Wiedenmann A (1983a) Expression of the fragile site Xq27 in fibroblasts. I. Detection of fra(X)(q27) in fibroblast clones from males with X-linked mental retardation. Hum Genet 63:404–405

    Google Scholar 

  • Steinbach P, Barbi G, Baur S, Vogel W (1983b) Expression of the fragile site Xq27 in fibroblasts. II. Evidence for negative and positive clones from heterozygous females and possible relationship between frequency and phenotype. Hum Genet 64:279–282

    Google Scholar 

  • Sutherland GR (1985) The enigma of the fragile×chromosome. Genetics 1:108–112

    Google Scholar 

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

    Google Scholar 

  • Sutherland GR, Baker E (1986) Effects of nucleotides on expression of the folate sensitive fragile sites. Am J Hum Genet 23:409–418

    MathSciNet  MATH  Google Scholar 

  • Suthers GK, Callen DF, Hyland VJ, Kozman HM, Baker E, Eyre H, Harper PS, Roberts SH, Hors-Cayla MC, Davies KE, Bell MV, Sutherland GR (1990) A new DNA marker tightly linked to the fragile×locus (FRAXA). Science 246:1298–1300

    Google Scholar 

  • Thibodeau SN, Dorkins HR, Faulk KR, Berry R, Smith ACM, Hagerman R, King A, Davies KE (1988) Linkage analysis using multiple DNA polymorphic markers in normal families and in families with fragile×syndrome. Hum Genet 79:219–227

    Google Scholar 

  • Tommerup N (1989) Cytogenetics of the fragile site at Xq27. In: Davies KE (ed) The fragile×syndrome. Oxford University Press, Oxford New York Tokyo, pp 102–135

    Google Scholar 

  • Tommerup N, Nielsen KB, Mikkelsen M (1981) Letter to the editor: marker×chromosome induction in fibroblasts by FUdR. Am J Med Genet 9:263–264

    Google Scholar 

  • Tommerup N, Aula P, Gustavii B, Heiberg A, Holmgren G, Koskull H von, Leisti J, Mikkelsen M, Mitelman F, Nielsen KB, Steinbach P, Stengel-Rutkowski S, Wahlström J, Zang K, Zang M (1986) Second trimester prenatal diagnosis of the fragile X. Am J Med Genet 23:313–324

    Google Scholar 

  • Veenema H, Geraedts JPM, Beverstock GC, Pearson PL (1987a) The fragile×syndrome in a large family. I. Cytogenetic and clinical investigations. J Med Genet 24:23–31

    Google Scholar 

  • Veenema H, Veenema T, Geraedts JPM (1987b) The fragile×syndrome in a large family. II. Psychological investigations. J Med Genet 24:32–38

    Google Scholar 

  • Voelckel MA, Philip N, Piquet C, Pellissier MC, Oberlé I, Birg F, Mattei MG, Mattei JF (1989) Study of a family with a fragile site of the×chromosome at Xq27–28 without mental retardation. Hum Genet 81:353–357

    Google Scholar 

  • Vogel W, Schempp W, Sigwarth I (1978) Comparison of thymidine, fluorodeoxyuridine, hydroxyurea, and methotrexate blocking at the G1/S phase transition of the cell cycle, studied by replication patterns. Hum Genet 45:183–198

    Google Scholar 

  • Webb TP (1989) The epidemiology of the fragile×syndrome. In: Davies KE (ed) The fragile×syndrome. Oxford University Press, Oxford New York Tokyo, pp 40–55

    Google Scholar 

  • Webb GC, Rogers JG, Pitt JG, Halliday J, Theobald T (1981) Transmission of the fragile (X)(q27) site from a normal male. Lancet II:1231–1232

    Google Scholar 

  • Webb TP, Bundey S, McKinley M (1989) Missed prenatal diagnosis of fragile×syndrome. Prenat Diagn 9:777–781

    Google Scholar 

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Authors and Affiliations

  1. Abteilung Klinische Genetik der Universität, Frauenstrasse 29, W-7900, Ulm, Germany

    Doris Wöhrle & Peter Steinbach

  2. Division of Human Genetics, University Hospital Gasthuisberg, B-3000, Leuven, Belgium

    Jean-Pierre Fryns

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  1. Doris Wöhrle
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  2. Jean-Pierre Fryns
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  3. Peter Steinbach
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Wöhrle, D., Fryns, JP. & Steinbach, P. Fragile×expression and×inactivation. Hum Genet 85, 659–665 (1990). https://doi.org/10.1007/BF00193594

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  • DOI: https://doi.org/10.1007/BF00193594

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