Abstract
The fragile X syndrome is caused by the amplification of a polymorphic CGG repeat in the 5′ untranslated region of the FMR1 gene and is the most common form of inherited mental retardation. When the repeat is amplified beyond 200 repeat units, the repeat and the FMR1 promoter region are methylated. As a result of this methylation the gene is silenced and no FMR1 gene product (FMRP) is translated. The lack of expression of FMRP in the fragile X syndrome causes the fragile X phenotype. A mouse model for the fragile X syndrome (knockout for FMRP) has been generated to study the pathological mechanisms leading to the symptoms seen in fragile X patients. FMRP is widely expressed in different tissues and localized predominantly in the cytoplasm associated with the 60S ribosomal subunit. The protein has RNA binding properties and possibly shuttles between cytoplasm and nucleus. The target signals necessary for this intracellular transport, like a nuclear location signal and a nuclear export signal, are present in FMRP. FMRP is also able to bind to other proteins by using specific sequence domains present in the protein. The coiled-coil structures formed by these domains are known to be involved in protein-protein interaction. In this review we postulate that FMRP is involved in the transport of RNA and/or proteins from the nucleus to the cytoplasm.
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REFERENCES
Ashley C Jr, Wilkinson KD, Reines D, et al (1993a) FMR1 protein: conserved RNP family domains and selective RNA binding. Science 262: 563–568.
Ashley CT, Sutcliffe JS, Kunst CB, et al (1993b) Human and murine FMR-1: alternative splicing and translational initiation downstream of the CGG-repeat. Nature Genet 4: 244–251.
Bächner D, Steinbach P, Wöhrle D, et al (1993) Enhanced Fmr-1 expression in testis. Nature Genet 4: 115–116.
Bakker CE, Verheij C, Willemsen R, et al (1994) Fmr1 knockout mice: a model to study fragile X mental retardation. Cell 78: 23–33.
Bennetto L, Pennington BF (1996) The neuropsychology of fragile X syndrome. In Hagerman RJ and Silverman AC, eds. The Neuropsychology of Fragile X Syndrome. Baltimore and London: The Johns Hopkins University Press, 210–250.
Butler MG, Brunswig A, Miller LK, et al (1992) Standards for selected anthropogenetic measurements in males with fragile X syndrome. Pediatrics 89: 1059–1062.
Coy JF, Sedlacek Z, Bachner D, et al (1995) Highly conserved 3'UTR and expression pattern of FXR1 points to a divergent gene regulation of FXR1 and FMR1. Hum Mol Genet 4: 2209–2218.
De Boulle K, Verkerk AJ, Reyniers E, et al (1993) A point mutation in the FMR-1 gene associated with fragile X mental retardation. Nature Genet 3: 31–35.
De Graaff E, Willemsen R, Zhong N, et al (1995) Instability of the CGG repeat and expression of the FMR1 protein in a male fragile X patient with a lung tumor. Am J Hum Genet 57: 609–618.
De Vries BBA, Jansen CAM, Duits AA, et al (1996) Variable FMR1 gene methylation leads to variable phenotype in 3 males from one fragile X family. J Med Genet, 33: 1007–1011.
Deelen W, Bakker C, Halley D, et al (1994) Conservation of CGG region in FMR1 gene in mammals. Am J Med Genet 51: 513–516.
Devys D, Lutz Y, Rouyer N, et al (1993) The FMR-1 protein is cytoplasmic, most abundant in neurons and appears normal in carriers of a fragile X premutation. Nature Genet 4: 335–340.
Eberhart DE, Malter HE, Feng Y, et al (1996) The fragile X mental retardation protein is a ribonucleoprotein containing both nuclear localization and nuclear export signals. Hum Mol Genet 5: 1083–1091.
Eichler EE, Richards S, Gibbs RA, et al (1993) Fine structure of the human FMR1 gene. Hum Mol Genet 2: 1147–1153.
Eichler EE, Holden J, Popovich BW, et al (1994) Length of uninterrupted CGG repeats determines instability in the FMR1 gene. Nature Genet 8: 88–94.
Feng Y, Zhang FP, Lokey LK, et al (1995) Translational suppression by trinucleotide repeat expansion at FMR1. Science 268: 731–734.
Francis R, Barton MK, Kimble J, et al (1995a) gld-1, a tumor suppressor gene required for oocyte development in Caenorhabditis elegans. Genetics 139: 579–606.
Francis R, Maine E, Schedl T (1995b) Analysis of the multiple roles of gld-1 in germline development: interactions with the sex determination cascade and the glp-1 signaling pathway. Genetics 139: 607–630.
Fryns JP (1989) Clinical studies. In Davies KE, ed. Clinical Studies. Oxford: Oxford University Press, 1–39.
Fu YH, Kuhl DP, Pizzuti A, et al (1991) Variation of the CGG repeat at the fragile X site results in genetic instability: resolution of the Sherman paradox. Cell 67: 1047–1058.
Hagerman RJ (1996) Physical and behavioral phenotype. In Hagerman RJ, Silverman AC, eds. The Neuropsychology of Fragile X Syndrome. Baltimore and London: The Johns Hopkins University Press, 3–87.
Hansen RS, Gartler SM, Scott CR, et al (1992) Methylation analysis of CGG sites in the CpG island of the human FMR1 gene. Hum Mol Genet 1: 571–578.
Hinds HL, Ashley CT, Sutcliffe JS, et al (1993) Tissue specific expression of FMR-1 provides evidence for a functional role in fragile X syndrome. Nature Genet 3: 36–43.
Hinton VJ, Brown WT, Wisniewski K, et al (1991) Analysis of neocortex in three males with the fragile X syndrome. Am J Med Genet 41: 289–294.
Jones AR, Schedl T (1995) Mutations in gld-1, a female germ cell-specific tumor suppressor gene in Caenorhabditis elegans, affect a conserved domain also found in Src-associated protein Sam68. Genes Dev 9: 1491–1504.
Khandjian EW, Fortin A, Thibodeau A, et al (1995) A heterogeneous set of FMR1 proteins is widely distributed in mouse tissues and is modulated in cell culture. Hum Mol Genet 4: 783–790.
Khandjian EW, Corbin F, Woerly S, et al (1996) The fragile X mental retardation protein is associated with ribosomes. Nature Genet 12: 91–93.
Kiledjian M, Dreyfuss G (1992) Primary structure and binding activity of the hnRNP U protein: binding RNA through RGG box. EMBO J 11: 2655–2664.
Kunst CB, Warren ST (1994) Cryptic and polar variation of the fragile X repeat could result in predisposing normal alleles. Cell 77: 853–861.
Musco G, Stier G, Joseph C, et al (1996) Three-dimensional structure and stability of the KH domain: molecular insights into the fragile X syndrome. Cell 85: 237–245.
Oberlé I, Rousseau F, Heitz D, et al (1991) Instability of a 550-base pair DNA segment and abnormal methylation in fragile X syndrome. Science 252: 1097–1102.
Ohno T, Ouchida M, Lee L, et al (1994) The EWS gene, involved in Ewing family of tumors, malignant melanoma of soft parts and desmoplastic small round cell tumors, codes for an RNA binding protein with novel regulatory domains. Oncogene 9: 3087–3097.
Oostra BA, Jacky PB, Brown WT, et al (1993) Guidelines for the diagnosis of fragile X syndrome. J Med Genet 30: 410–413.
Pieretti M, Zhang FP, Fu YH, et al (1991) Absence of expression of the FMR-1 gene in fragile X syndrome. Cell 66: 817–822.
Price DK, Zhang F, Ashley CTJ, et al (1996) The chicken FMR1 gene is highly conserved with a CCT 5′-untranslated repeat and encodes an RNA-binding protein. Genomics 31: 3–12.
Purpura RP (1974) Dendritic spine dysgenesis and mental retardation. Science 186: 1126–1128.
Rousseau F, Heitz D, Biancalana V, et al (1991) Direct diagnosis by DNA analysis of the fragile X syndrome of mental retardation. N Engl J Med 325: 1673–1681.
Rousseau F, Robb LJ, Rouillard P, et al (1994) No mental retardation in a man with 40% abnormal methylation at the FMR-1 locus and transmission of sperm cell mutations as premutations. Hum Mol Genet 3: 927–930.
Rudelli RD, Brown WT, Wisniewski K, et al (1985) Adult fragile X syndrome. Cliniconeuropathologic findings. Acta Neuropathol 67: 289–295.
Sherman SL, Jacobs PA, Morton NE, et al (1994) Further segregation analysis of the fragile X syndrome with special reference to transmitting males. Hum Genet 69: 289–299.
Siomi H, Siomi MC, Nussbaum RL, et al (1993) The protein product of the fragile X gene, FMR1, has characteristics of an RNA-binding protein. Cell 74: 291–298.
Siomi H, Choi M, Siomi MC, et al (1994) Essential role for KH domains in RNA binding: impaired RNA binding by a mutation in the KH domain of FMR1 that causes fragile X syndrome. Cell 77: 33–39.
Siomi MC, Siomi H, Sauer WH, et al (1995) FXR1, an autosomal homologue of the fragile X mental retardation gene. EMBO J, 14: 2401–2408.
Siomi MC, Zhang Y, Siomi H, et al (1996) Specific sequences in the fragile X syndrome FMR1 protein and the FXR proteins mediate their binding to 60S ribosomal subunits and the interactions among them. Mol Cell Biol 16: 3825–3832.
Sittler A, Devys D, Weber C, et al (1996) Alternative splicing of exon 14 determines nuclear or cytoplasmic localisation of FMR1 protein isoforms. Hum Mol Genet 5: 95–102.
Smeets H, Smits A, Verheij CE, et al (1995) Normal phenotype in two brothers with a full FMR1 mutation. Hum Mol Genet 4: 2103–2108.
Snudden DK, Hearing J, Smith PR, et al (1994) EBNA-1, the major nuclear antigen of Epstein-Barr virus, resembles ‘RGG’ RNA binding proteins. EMBO J 13: 4840–4847.
Tamanini F, Meijer N, Verheij C, et al (1996) FMRP is associated to the ribosomes via RNA. Hum Mol Genet 5: 809–813.
Turner G, Webb T, Wake S, et al (1996) The prevalence of the fragile X syndrome. Am J Med Genet 64: 196–197.
Verheij C, Bakker CE, de Graaff E, et al (1993) Characterization and localization of the FMR-1 gene product associated with fragile X syndrome. Nature 363: 722–724.
Verheij C, De Graaff E, Bakker CE, et al (1995) Characterization of FMR1 proteins isolated from different tissues. Hum Mol Genet 4: 895–901.
Verkerk AJ, Pieretti M, Sutcliffe JS, et al (1991) 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.
Verkerk AJ, De Graaff E, De Boulle K, et al (1993) Alternative splicing in the fragile X gene FMR1. Hum Mol Genet 2: 399–404.
Wells RD (1996) Molecular basis of genetic instability of triplet repeats. J Biol Chem 271: 2875–2878.
Willemsen R, Mohkamsing S, De Vries B, et al (1995) Rapid antibody test for fragile X syndrome. Lancet 345: 1147–1148.
Willemsen R, Bontekoe C, Tamanini F, et al (1996) Association of FMRP with ribosomal precursor particles in the nucleolus. Biochem Biophys Res Commun 225: 27–33.
Zhang Y, Oconnor JP, Siomi MC, et al (1995) The fragile X mental retardation syndrome protein interacts with novel homologs FXR1 and FXR2. EMBO J 14: 5358–5366.
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Hoogeveen, A.T., Oostra, B.A. The fragile X syndrome. J Inherit Metab Dis 20, 139–151 (1997). https://doi.org/10.1023/A:1005392319533
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DOI: https://doi.org/10.1023/A:1005392319533