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The FMR–1 protein is cytoplasmic, most abundant in neurons and appears normal in carriers of a fragile X premutation

Abstract

Fragile X mental retardation syndrome is caused by the unstable expansion of a CGG repeat in the FMR–1 gene. In patients with a full mutation, abnormal methylation results in suppression of FMR–1 transcription. FMR–1 is expressed in many tissues but its function is unknown. We have raised monoclonal antibodies specific for the FMR–1 protein. They detect 4–5 protein bands which appear identical in cells of normal males and of males carrying a premutation, but are absent in affected males with a full mutation. Immunohistochemistry shows a cytoplasmic localization of FMR–1. The highest levels were observed in neurons, while glial cells contain very low levels. In epithelial tissues, levels of FMR–1 were higher in dividing layers. In adult testis, FMR–1 was detected only in spermatogonia. FMR–1 was not detected in dermis and cardiac muscle except under pathological conditions.

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References

  1. Sherman, S. Recognition of the fragile X or Martin-Bell syndrome. In Fragile X syndrome: diagnosis, treatment and research. (eds Hagerman, R.J. & Silverman A.C.) 69–97 (The Johns Hopkins University Press, Baltimore, 1991).

    Google Scholar 

  2. Sutherland, G.R. Fragile sites on human chromosomes: demonstration of their dependence on the type of tissue culture medium. Science 197, 265–266 (1977).

    Article  CAS  PubMed  Google Scholar 

  3. Hagermann et al. Physical and behavioral phenotype. In Fragile Xsyndrome: diagnosis, treatment and research. (eds Hagerman, R.J. & Silverman A.C.) 3–68 (The Johns Hopkins University Press, Baltimore, 1991).

    Google Scholar 

  4. Sherman, S.L. et al. Further segragation analysis of the fragile X syndrome with special reference to transmitting males. Hum. Genet. 69, 289–299 (1985).

    Article  CAS  PubMed  Google Scholar 

  5. Oberlé, I. et al. Instability of a 550-base pair DNA segment and abnormal methylation in fragile X syndrome. Science 252, 1097–1102 (1991).

    Article  PubMed  Google Scholar 

  6. Yu, S. et al. Fragile X genotype characterized by an unstable region of DNA. Science 252, 1179–1181 (1991).

    Article  CAS  PubMed  Google Scholar 

  7. Kremer, E.J. et al. Mapping of DNA instability at the fragile X to a trinucleotide repeat sequence p(CCG)n. Science 252, 1711–1714 (1991).

    Article  CAS  PubMed  Google Scholar 

  8. Verkerk, A.J.M.H. et al. Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell 65, 905–914 (1991).

    Article  CAS  PubMed  Google Scholar 

  9. Fu, Y.-H. et al. Variation of the CGG repeat at the fragile X site results in genetic instability: resolution of the Sherman paradox. Cell 67, 1047–1058 (1991).

    Article  CAS  PubMed  Google Scholar 

  10. Rousseau, F. et al. Direct diagnosis by DNA analysis of the fragile X syndrome of mental retardation. New Engl. J. Med. 325, 1673–1681 (1991).

    Article  CAS  PubMed  Google Scholar 

  11. Hansen, R.S., Gartler, S.M., Scott, C.R., Chen, S. & Laird, C.D. Methylation analysis of CGG sites in the CpG island of the human FMR1 gene. Hum. molec. Gen. 1, 571–578 (1992).

    Article  CAS  Google Scholar 

  12. Yu, S. et al. Fragile-X syndrome: unique genetics of the heritable unstable element. Am. J. hum. Genet. 50, 968–980 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Heitz, D., Devys, D., Imbert, G., Kretz, C. & Mandel, J.L. Inheritance of the fragile X syndrome: size of the fragile X premutation is a major determinant of the transition to full mutation. J. med. Genet. 29, 794–801 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Pieretti, M. et al. Abscence of expression of the FMR-1 gene in fragile X syndrome. Cell 66, 817–822 (1991).

    Article  CAS  PubMed  Google Scholar 

  15. Sutcliffe, J.S. et al. DNA methylation represses FMR-1 transcription in fragile X syndrome. Hum. molec. Gen. 1, 397–400 (1992).

    Article  CAS  Google Scholar 

  16. Wohrle, D. et al. A microdeletion of less than 250kb, including the proximal part of the FMR-1 gene and the fragile X site, in a male with the clinical phenotype of fragile X syndrome. Am. J. hum. Genet. 51, 299–306 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Gedeon, A.K. et al. Fragile X syndrome without CCG amplification has an FMR1 deletion. Nature Genet. 1, 341–344 (1992).

    Article  CAS  PubMed  Google Scholar 

  18. De Boulle, K. et al. A point mutation in the FMR-1 gene associated with fragile X mental retardation. Nature Genet. 3, 31–35 (1993).

    Article  CAS  PubMed  Google Scholar 

  19. Hinds, H.L. et al. Tissue specific expression of FMR-1 provides evidence for a functional role in fragile X syndrome. Nature Genet. 3, 36–43 (1993).

    Article  CAS  PubMed  Google Scholar 

  20. Dieckmann, C.L. & Tzagoloff, A. Assembly of the mitochondrial membrane system. CBP6, a yeast nuclear gene necessary for synthesis of cytochrome b. J. Biol. Chem. 260, 1513–1520 (1985).

    CAS  PubMed  Google Scholar 

  21. Green, S. et al. Human oestrogen receptor cDNA: sequence, expression and homology to v-erb-A.. Nature 320, 134–139 (1986).

    Article  CAS  PubMed  Google Scholar 

  22. Ashley, C.T. et al. Human and murine FMR-1 : alternative splicing and translational initiation downstream of the CGG-repeat. Nature genet. 4, 244–251 (1993).

    Article  CAS  PubMed  Google Scholar 

  23. Verkerk, A.J.M.H. et al. Alternative splicing in the fragile X gene FMR1. Hum. molec. Gen. 2, 399–404 (1993).

    Article  CAS  Google Scholar 

  24. Abitbol, M. et al. Nucleus basalis magnocellularis and hippocampus are the major sites of FMR-1 expression in the human fetal brain. Nature genet. 4, 148–152 (1993).

    Article  Google Scholar 

  25. Reiss, A.L., Aylward, E., Freund, L., Bryan, N. & Joshi, P. Neuroanatomy of fragile X syndrome: the posterior fossa. Ann. Neurol. 29, 26–32 (1991).

    Article  CAS  PubMed  Google Scholar 

  26. Johannisson, R., Rehder, H., Wendt, V. & Schwinger, E. Spermatogenesis in two patients with the fragile X syndrome. I. Histology: light and electron microscopy. Hum. Genet. 76, 141–147 (1987).

    Article  CAS  PubMed  Google Scholar 

  27. Johannisson, R., Froster-lskenius, U., Saadallah, N. & Hulten, M.A. Spermatogenesis in two patients with the fragile X syndrome. II. First meiosis: light and electron microscopy. Hum. Genet. 79, 231–234 (1988).

    Article  CAS  PubMed  Google Scholar 

  28. Reyniers, E. et al. The full mutation in the FMR-1 gene of male fragile X patients is absent in their sperm. Nature genet. 4, 143–146 (1993).

    Article  CAS  PubMed  Google Scholar 

  29. Berry-Kravis, E. & Huttenlocher, P.R. Cyclic AMP metabolism in fragile X syndrome. Ann. Neurol. 31, 22–26 (1992).

    Article  CAS  PubMed  Google Scholar 

  30. Kastner, P. et al. Structure, localization and transcriptional properties of two classes of retinoic acid receptor a fusion proteins in acute promyelocytic leukemia (APL): stuctural similarities with a new family of oncoproteins. EMBO J. 11, 629–42 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Bradford, M.M. A rapid and sensitive method for the quantification of microgram quantities of proteins utilizing the principle of protein-dye binding. Anal. Biochem. 72, 248–254 (1976).

    Article  CAS  PubMed  Google Scholar 

  32. St Groth, F.S. & Scheidegger, D. Production of monoclonal antibodies: strategy and tools. J. Immunol. Methods 35, 1–21 (1986).

    Article  Google Scholar 

  33. Brou, C. et al. Distinct TF II D complexes mediate the effect of different transcriptional activities. EMBO J. 12, 489–499 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Gorman, C. High efficiency gene transfer into mamalian cells. In DNA cloning Vol. 2 (ed. Glover, D.M.) 143–190 (IRL Press, Washington, 1985).

    Google Scholar 

  35. Harlow, E. & Lane, D. Antibodies: A Laboratory Manual (Cold Spring Harbor Press, New York, 1988).

    Google Scholar 

  36. Mantovani, R. et al. Monoclonal antibodies to NF-Y define its function in MHC class II and albumin gene transcription. EMBO J. 11, 3315–3322 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Devys, D., Lutz, Y., Rouyer, N. et al. The FMR–1 protein is cytoplasmic, most abundant in neurons and appears normal in carriers of a fragile X premutation. Nat Genet 4, 335–340 (1993). https://doi.org/10.1038/ng0893-335

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