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The Molecular Biology of FXTAS

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The Fragile X-Associated Tremor Ataxia Syndrome (FXTAS)

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Abstract

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late adult onset neurodegenerative disorder that affects many individuals, mostly males, carriers of a premutation CGG repeat expansion in the FMR1 gene (55–200 CGG repeats). FXTAS symptoms include progressive intention tremor, gait ataxia, neuropathy, psychiatric symptoms, cognitive decline, and autonomic dysfunctions. The disorder is due to an RNA gain-of-function mechanism, which has also been implicated in other non-coding repeat expansion diseases, as elevated FMR1 mRNA expression levels have been observed in premutation carriers. The mechanism is very distinct from the complete transcriptional silencing of the FMR1 gene that causes fragile X syndrome. The severity of both clinical and neuropathological phenotypes, including intranuclear inclusions throughout the brain, the neuropathological hallmark of FXTAS, appears to be positively correlated with the size of the CGG repeat expansion. Disruption of the lamin A/C nuclear architecture, seen in other neuromuscular disorders, has also been reported in FXTAS and could be linked to clinical features of FXTAS, particularly peripheral neuropathy.

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References

  • Adams, J. S., Adams, P. E., Nguyen, D., Brunberg, J. A., Tassone, F., Zhang, W., Koldewyn, K., Rivera, S. M., Grigsby, J., Zhang, L. 2007. Volumetric brain changes in females with fragile X-associated tremor/ataxia syndrome (FXTAS). Neurology 69: 851.

    Article  PubMed  CAS  Google Scholar 

  • Allen, E. G., Sherman, S., Abramowitz, A., Leslie, M., Novak, G., Rusin, M., Scott, E., Letz, R. 2005. Examination of the effect of the polymorphic CGG repeat in the FMR1 gene on cognitive performance. Behav Genet 35: 435–445.

    Article  PubMed  Google Scholar 

  • Arocena, D. G., Iwahashi, C. K., Won, N., Beilina, A., Ludwig, A. L., Tassone, F., Schwartz, P. H., Hagerman, P. J. 2005. Induction of inclusion formation and disruption of lamin A/C structure by premutation CGG-repeat RNA in human cultured neural cells. Hum Mol Genet 14: 3661–3671.

    Article  PubMed  CAS  Google Scholar 

  • Arocena, D., Yang, J. E., Brouwer, J. R., Tassone, F., Iwahashi, C., Berry-Kravis, E. M., Goetz, C. G., Sumis, A. M., Zhou, L., Nguyen, D., Yang, Y., Howell, E., Ludwig, A., Greco, C., Willemsen, R., Hagerman, R. J., Hagerman, P. J. Fibroblast phenotype in male carriers of FMR1 premutation alleles. Hum Mol Genet 2010, 19(2): 299–312.

    Google Scholar 

  • Ashley, C. T., Wilkinson, K. D., Reines, D., Warren, S. T. 1993. FMR1 protein: conserved RNP family domains and selective RNA binding. Science 262: 563–566.

    Article  PubMed  CAS  Google Scholar 

  • Beilina, A., Tassone, F., Schwartz, P. H., Sahota, P., Hagerman, P. J. 2004. Redistribution of transcription start sites within the FMR1 promoter region with expansion of the downstream CGG-repeat element. Hum Mol Genet 13: 543–549.

    Article  PubMed  CAS  Google Scholar 

  • Berry-Kravis, E., Lewin, F., Wuu, J., Leehey, M., Hagerman, R., Hagerman, P., Goetz, C. G. 2003. Tremor and ataxia in fragile X premutation carriers: blinded videotape study. Ann Neurol 53: 616–623.

    Article  PubMed  CAS  Google Scholar 

  • Berry-Kravis, E., Potanos, K., Weinberg, D., Zhou, L., Goetz, C. G. 2005. Fragile X-associated tremor/ataxia syndrome in sisters related to X-inactivation. Ann Neurol 57: 144–147.

    Article  PubMed  CAS  Google Scholar 

  • Berry-Kravis, E., Abrams, L., Coffey, S., Hall, D., Greco, C., Gane, L., Grigsby, J., Bourgeois, J., Finucane, B., Jacquemont, S., Brunberg, J., Zhang, L., Lin, J., Tassone, F., Hagerman, P., Hagerman, R., Leehey, M. 2007. Fragile X-associated tremor/ataxia syndrome: clinical features, genetics, and testing guidelines. Mov Disord 22: 2018.

    Article  PubMed  Google Scholar 

  • Chen, L. S., Tassone, F., Sahota, P., Hagerman, P. J. 2003. The (CGG) n repeat element within the 5ʹ untranslated region of the FMR1 message provides both positive and negative cis effects on in vivo translation of a downstream reporter. Hum Mol Genet 12: 3067–3074.

    Article  PubMed  CAS  Google Scholar 

  • Chow, C. W., Clark, M. P., Rinaldo, J. E., Chalkley, R. 1995. Multiple initiators and C/EBP binding sites are involved in transcription from the TATA-less rat XDH/XO basal promoter. Nucleic Acids Res 23: 3132–3140.

    Article  PubMed  CAS  Google Scholar 

  • Coffey, S. M., Cook, K., Tartaglia, N., Tassone, F., Nguyen, D. V., Pan, R., Bronsky, H. E., Yuhas, J., Borodyanskaya, M., Grigsby, J. 2008. Expanded clinical phenotype of women with the FMR1 premutation. Am J Med Genet A 146A(8): 1009–1016.

    Article  PubMed  Google Scholar 

  • Cohen, S., Masyn, K., Adams, J., Hessl, D., Rivera, S., Tassone, F., Brunberg, J., DeCarli, C., Zhang, L., Cogswell, J. 2006. Molecular and imaging correlates of the fragile X-associated tremor/ataxia syndrome. Neurology 67: 1426.

    Article  PubMed  CAS  Google Scholar 

  • Cornish, K. M., Manly, T., Savage, R., Swanson, J., Morisano, D., Butler, N., Grant, C., Cross, G., Bentley, L., Hollis, C. P. 2005. Association of the dopamine transporter (DAT1) 10/10-repeat genotype with ADHD symptoms and response inhibition in a general population sample. Mol Psychiatry 10: 686–698.

    Article  PubMed  CAS  Google Scholar 

  • Crawford, D. C., Meadows, K. L., Newman, J. L., Taft, L. F., Scott, E., Leslie, M., Shubek, L., Holmgreen, P., Yeargin-Allsopp, M., Boyle, C. 2002. Prevalence of the fragile X syndrome in African-Americans. Am J Med Genet 110: 226–233.

    Article  PubMed  Google Scholar 

  • de Vries, B. B., van den Ouweland, A. M., Mohkamsing, S., Duivenvoorden, H. J., Mol, E., Gelsema, K., van Rijn, M., Halley, D. J., Sandkuijl, L. A., Oostra, B. A., Tibben, A., Niermeijer, M. F. 1997. Screening and diagnosis for the fragile X syndrome among the mentally retarded: an epidemiological and psychological survey. Collaborative Fragile X study Group. Am J Hum Genet 61: 660–667.

    Article  PubMed  Google Scholar 

  • Dombrowski, C., Levesque, S., Morel, M. L., Rouillard, P., Morgan, K., Rousseau, F. 2002. Premutation and intermediate-size FMR1 alleles in 10 572 males from the general population: loss of an AGG interruption is a late event in the generation of fragile X syndrome alleles. Hum Mol Genet 11: 371–378.

    Article  PubMed  CAS  Google Scholar 

  • Eichler, E. E., Richards, S., Gibbs, R. A., Nelson, D. L. 1993. Fine structure of the human FMR1 gene. Hum Mol Genet 2: 1147–1153.

    Article  PubMed  CAS  Google Scholar 

  • Farzin, F., Perry, H., Hessl, D., Loesch, D., Cohen, J., Bacalman, S., Gane, L., Tassone, F., Hagerman, P., Hagerman, R. 2006. Autism spectrum disorders and attention-deficit/ hyperactivity disorder in boys with the fragile X permutation. J Dev Behav Pediatr 27: S137–144.

    Article  PubMed  Google Scholar 

  • Fernandez-Carvajal, I., Walichiewicz, P., Xiaosen, X., Pan, R., Hagerman, P., Tassone, F. 2009. Screening for expanded alleles of the FMR1 gene in blood spots from newborn males in a Spanish population. J Mol Diagn 11(4): 324–329 (in press). Epub 2009 May 21.

    Article  PubMed  CAS  Google Scholar 

  • Finsterer, J. 2002. Myotonic dystrophy type 2. Eur J Neurol 9: 441–447.

    Article  PubMed  CAS  Google Scholar 

  • Fu, Y. H., Kuhl, D. P., Pizzuti, A., Pieretti, M., Sutcliffe, J. S., Richards, S., Verkerk, A. J., Holden, J. J., Fenwick, R. G., Jr., Warren, S. T., Oostra, B. A., Nelson, D. L., Caskey, C. T. 1991. Variation of the CGG repeat at the fragile X site results in genetic instability: resolution of the Sherman paradox. Cell 67: 1047–1058.

    Article  PubMed  CAS  Google Scholar 

  • Goodlin-Jones, B., Tassone, F., Gane, L. W., Hagerman, R. J. 2004. Autistic spectrum disorder and the fragile X premutation. J Dev Behav Pediatr 25: 392–398.

    Article  PubMed  Google Scholar 

  • Greco, C. M., Hagerman, R. J., Tassone, F., Chudley, A. E., Del Bigio, M. R., Jacquemont, S., Leehey, M., Hagerman, P. J. 2002. Neuronal intranuclear inclusions in a new cerebellar tremor/ataxia syndrome among fragile X carriers. Brain 125: 1760.

    Article  PubMed  CAS  Google Scholar 

  • Greco, C. M., Berman, R. F., Martin, R. M., Tassone, F., Schwartz, P. H., Chang, A., Trapp, B. D., Iwahashi, C., Brunberg, J., Grigsby, J., Hessl, D., Becker, E. J., Papazian, J., Leehey, M. A., Hagerman, R. J., Hagerman, P. J. 2006. Neuropathology of fragile X-associated tremor/ataxia syndrome (FXTAS). Brain 129: 243–255.

    Article  PubMed  CAS  Google Scholar 

  • Greco, C. M., Soontrapornchai, K., Wirojanan, J., Gould, J. E., Hagerman, P. J., Hagerman, R. J. 2007. Testicular and pituitary inclusion formation in fragile X associated tremor/ataxia syndrome. J Urol 177: 1434–1437.

    Article  PubMed  CAS  Google Scholar 

  • Greco, C. M., Tassone, F., Garcia-Arocena, D., Tartaglia, N., Coffey, S. M., Vartanian, T. K., Brunberg, J. A., Hagerman, P. J., Hagerman, R. J. 2008. Clinical and neuropathologic findings in a woman with the FMR1 premutation and multiple sclerosis. Arch Neurol 65: 1114.

    Article  PubMed  Google Scholar 

  • Gusella, J. F., MacDonald, M. E. 2000. Molecular genetics: unmasking polyglutamine triggers in neurodegenerative disease. Nat Rev Neurosci 1: 109–115.

    Article  PubMed  CAS  Google Scholar 

  • Hagerman, P. 2008. The fragile X prevalence paradox. J Med Genet 45: 498–499.

    Article  PubMed  Google Scholar 

  • Hagerman, P. J., Hagerman, R. J. 2004a. The fragile-X premutation: a maturing perspective. Am J Hum Genet 74: 805–816.

    Article  PubMed  CAS  Google Scholar 

  • Hagerman, P. J., Hagerman, R. J. 2004b. Fragile X-associated tremor/ataxia syndrome (FXTAS). Ment Retard Dev Disabil Res Rev 10: 25–30.

    Article  PubMed  Google Scholar 

  • Hagerman, R. J., Leehy, M., Heinrichs, W., Tassone, F., Wilson, R., Hills, J., Grigsby, J., Gage, B., Hagerman, P. 2001. Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X. Neurology 57: 127–130.

    Article  PubMed  CAS  Google Scholar 

  • Hagerman, R. J., Leavitt, B. R., Farzin, F., Jacquemont, S., Greco, C. M., Brunberg, J. A., Tassone, F., Hessl, D., Harris, S. W., Zhang, L. 2004a. Fragile-X–associated tremor/ataxia syndrome (FXTAS) in females with the FMR1 premutation. Am J Hum Genet 74: 1051–1056.

    Article  PubMed  CAS  Google Scholar 

  • Hagerman, R. J., Leavitt, B. R., Farzin, F., Jacquemont, S., Greco, C. M., Brunberg, J. A., Tassone, F., Hessl, D., Harris, S. W., Zhang, L., Jardini, T., Gane, L. W., Ferranti, J., Ruiz, L., Leehey, M. A., Grigsby, J., Hagerman, P. J. 2004b. Fragile-X-associated tremor/ataxia syndrome (FXTAS) in females with the FMR1 premutation. Am J Hum Genet 74: 1051–1056.

    Article  PubMed  CAS  Google Scholar 

  • Hagerman, R. J., Coffey, S. M., Maselli, R., Soontarapornchai, K., Brunberg, J. A., Leehey, M. A., Zhang, L., Gane, L. W., Fenton-Farrell, G., Tassone, F., Hagerman, P. J. 2007. Neuropathy as a presenting feature in fragile X-associated tremor/ataxia syndrome. Am J Med Genet A 143: 2256–2260.

    Google Scholar 

  • Hinds, H. L., Ashley, C. T., Sutcliffe, J. S., Nelson, D. L., Warren, S. T., Housman, D. E., Schalling, M. 1993. Tissue specific expression of FMR–1 provides evidence for a functional role in fragile X syndrome. Nat Genet 3: 36–43.

    Article  PubMed  CAS  Google Scholar 

  • Holaska, J. M., Kowalski, A. K., Wilson, K. L. 2004. Emerin caps the pointed end of actin filaments: evidence for an actin cortical network at the nuclear inner membrane. PLoS Biol 2: e231.

    Article  PubMed  Google Scholar 

  • Huang, T., Li, L. Y., Shen, Y., Qin, X. B., Pang, Z. L., Wu, G. Y. 1996. Alternative splicing of the FMR1 gene in human fetal brain neurons. Am J Med Genet 64: 252–255.

    Article  PubMed  CAS  Google Scholar 

  • Hundscheid, R. D., Smits, A. P., Thomas, C. M., Kiemeney, L. A., Braat, D. D. 2003. Female carriers of fragile X premutations have no increased risk for additional diseases other than premature ovarian failure. Am J Med Genet 117(1): 6–9.

    Article  Google Scholar 

  • Iwahashi, C. K., Yasui, D. H., An, H. J., Greco, C. M., Tassone, F., Nannen, K., Babineau, B., Lebrilla, C. B., Hagerman, R. J., Hagerman, P. J. 2006. Protein composition of the intranuclear inclusions of FXTAS. Brain 129: 256.

    Article  PubMed  CAS  Google Scholar 

  • Jacquemont, S., Hagerman, R. J., Leehey, M., Grigsby, J., Zhang, L., Brunberg, J. A., Greco, C., Des Portes, V., Jardini, T., Levine, R. 2003. Fragile X premutation tremor/ataxia syndrome: molecular, clinical, and neuroimaging correlates. Am J Hum Genet 72: 869–878.

    Article  PubMed  CAS  Google Scholar 

  • Jacquemont, S., Farzin, F., Hall, D., Leehey, M., Tassone, F. 2004. Aging in individuals with the FMR1 mutation. Am J Ment Retard 109: 154–164.

    Article  PubMed  CAS  Google Scholar 

  • Jacquemont, S., Orrico, A., Galli, L., Sahota, P. K., Brunberg, J. A., Anichini, C., Leehey, M., Schaeffer, S., Hagerman, R. J., Hagerman, P. J. 2005. Spastic paraparesis, cerebellar ataxia, and intention tremor: a severe variant of FXTAS? J Med Genet 42: e14.

    Article  PubMed  CAS  Google Scholar 

  • Jacquemont, S., Leehey, M. A., Hagerman, R. J., Beckett, L. A., Hagerman, P. J. 2006. Size bias of fragile X premutation alleles in late-onset movement disorders. Journal of medical genetics 43: 804–809.

    Article  Google Scholar 

  • Javahery, R., Khachi, A., Lo, K., Zenzie-Gregory, B., Smale, S. T. 1994. DNA sequence requirements for transcriptional initiator activity in mammalian cells. Mol Cell Biol 14: 116–127.

    PubMed  CAS  Google Scholar 

  • Jenkins, E. C., Velinov, M. T., Ye, L., Gu, H., Li, S., Brooks, S. S., Pang, D., Devenny, D. A., Zigman, W. B. 2006. Telomere shortening in T lymphocytes of older individuals with Down syndrome and dementia. Neurobiol Aging 27: 941–945.

    Article  PubMed  CAS  Google Scholar 

  • Jenkins, E. C., Tassone, F., Ye, L., Gu, H., Xi, M., Velinov, M., Brown, W. T., Hagerman, R. J., Hagerman, P. J. 2008. Reduced telomere length in older men with premutation alleles of the fragile X mental retardation 1 gene. Am J Med Genet A 146: 1543–1546.

    Google Scholar 

  • Jin, P., Warren, S. T. 2000. Understanding the molecular basis of fragile X syndrome. Hum Mol Genet 9(6): 901–908.

    Article  PubMed  CAS  Google Scholar 

  • Jin, P., Zarnescu, D. C., Zhang, F., Pearson, C. E., Lucchesi, J. C., Moses, K., Warren, S. T. 2003. RNA-mediated neurodegeneration caused by the fragile X premutation rCGG repeats in drosophila. Neuron 39: 739–747.

    Article  PubMed  CAS  Google Scholar 

  • Jung, T., Catalgol, B., Grune, T. 2009. The proteasomal system. Mol Aspects Med 30: 191–296.

    Article  PubMed  CAS  Google Scholar 

  • Kenneson, A., Zhang, F., Hagedorn, C. H., Warren, S. T. 2001. Reduced FMRP and increased FMR1 transcription is proportionally associated with CGG repeat number in intermediate-length and premutation carriers. Hum Mol Genet 10: 1449.

    Article  PubMed  CAS  Google Scholar 

  • Khalil, A. M., Faghihi, M. A., Modarresi, F., Brothers, S. P., Wahlestedt, C. 2008. A novel RNA transcript with antiapoptotic function is silenced in fragile X syndrome. PLoS One 3: e1486.

    Google Scholar 

  • Kunst, C. B., Warren, S. T. 1994. Cryptic and polar variation of the fragile X repeat could result in predisposing normal alleles. Cell (Cambridge) 77: 853–861.

    Article  CAS  Google Scholar 

  • Ladd, P. D., Smith, L. E., Rabaia, N. A., Moore, J. M., Georges, S. A., Hansen, R. S., Hagerman, R. J., Tassone, F., Tapscott, S. J., Filippova, G. N. 2007. An antisense transcript spanning the CGG repeat region of FMR1 is upregulated in premutation carriers but silenced in full mutation individuals. Hum Mol Genet 16: 3174–3187.

    Article  PubMed  CAS  Google Scholar 

  • Leehey, M. A., Berry-Kravis, E., Min, S. J., Hall, D. A., Rice, C. D., Zhang, L., Grigsby, J., Greco, C. M., Reynolds, A., Lara, R. 2007. Progression of tremor and ataxia in male carriers of the FMR1 premutation. Mov Disord (New York) 22: 203.

    Article  Google Scholar 

  • Libotte, T., Zaim, H., Abraham, S., Padmakumar, V. C., Schneider, M., Lu, W., Munck, M., Hutchison, C., Wehnert, M., Fahrenkrog, B. 2005. Lamin A/C-dependent localization of nesprin-2, a giant scaffolder at the nuclear envelope. Mol Biol Cell 16: 3411–3424.

    Article  PubMed  CAS  Google Scholar 

  • Lin, F., Worman, H. J. 1993. Structural organization of the human gene encoding nuclear lamin A and nuclear lamin C. J Biol Chem 268: 16321–16326.

    PubMed  CAS  Google Scholar 

  • Loesch, D. Z., Churchyard, A., Brotchie, P., Marot, M., Tassone, F. 2005. Evidence for, and a spectrum of, neurological involvement in carriers of the fragile X pre-mutation: FXTAS and beyond. Clin Genet 67: 412–417.

    Article  PubMed  CAS  Google Scholar 

  • Ludwig, A. L., Raske, C., Tassone, F., Garcia-Arocena, D., Hershey, J. W., Hagerman, P. J. 2009. Translation of the FMR1 mRNA is not influenced by AGG interruptions. Nucleic Acids Res 37: 6896–6904.

    Article  PubMed  CAS  Google Scholar 

  • Maddalena, A., Richards, C. S., McGinniss, M. J., Brothman, A., Desnick, R. J., Grier, R. E., Hirsch, B., Jacky, P., McDowell, G. A., Popovich, B. 2001. Technical standards and guidelines for fragile X: the first of a series of disease-specific supplements to the standards and guidelines for clinical genetics laboratories of the American college of medical genetics. Genet Med 3: 200.

    Article  PubMed  CAS  Google Scholar 

  • Mankodi, A., Thornton, C. A. 2002. Myotonic syndromes. Curr Opin Neurol 15: 545.

    Article  PubMed  Google Scholar 

  • Mankodi, A., Logigian, E., Callahan, L., McClain, C., White, R., Henderson, D., Krym, M., Thornton, C. A. 2000. Myotonic dystrophy in transgenic mice expressing an expanded CUG repeat. Science 289(5485): 1769–1772.

    Article  PubMed  CAS  Google Scholar 

  • Morton, J. E., Bundey, S., Webb, T. P., MacDonald, F., Rindl, P. M., Bullock, S. 1997. Fragile X syndrome is less common than previously estimated. J Med Genet 34: 1–5.

    Article  PubMed  CAS  Google Scholar 

  • Nolin, S. L., Brown, W. T., Glicksman, A., Houck, G. E., Gargano, A. D., Sullivan, A., Biancalana, V., Brondum-Nielsen, K., Hjalgrim, H., Holinski-Feder, E., Kooy, F., Longshore, J., Macpherson, J., Mandel, J. L., Matthijs, G., Rousseau, F., Steinbach, P., Vaisanen, M. L., von Koskull, H., Sherman, S. 2003. Expansion of the fragile X CGG repeat in females with premutation or intermediate alleles. Am J Hum Genet 72: 454–464.

    Article  PubMed  CAS  Google Scholar 

  • Oberle, I., Rousseau, F., Heitz, D., Kretz, C., Devys, D., Hanauer, A., Boue, J., Bertheas, M. F., Mandel, J. L. 1991. Instability of a 550-base pair DNA segment and abnormal methylation in fragile X syndrome. Science 252: 1097–1102.

    Article  CAS  Google Scholar 

  • Orr, H. T., Zoghbi, H. Y. 2001. SCA1 molecular genetics: a history of a 13 year collaboration against glutamines. Hum Mol Genet 10: 2307–2311.

    Article  PubMed  CAS  Google Scholar 

  • Panossian, L., Porter, V., Valenzuela, H., Zhu, X., Reback, E., Masterman, D., Cummings, J., Effros, R. 2003. Telomere shortening in T cells correlates with Alzheimer’s disease status. Neurobiol Aging 24: 77–84.

    Article  PubMed  CAS  Google Scholar 

  • Pesso, R., Berkenstadt, M., Cuckle, H., Gak, E., Peleg, L., Frydman, M., Barkai, G. 2000. Screening for fragile X syndrome in women of reproductive age. Prenat Diagn 20: 611–614.

    Article  PubMed  CAS  Google Scholar 

  • Peters, N., Kamm, C., Asmus, F., Holinski-Feder, E., Kraft, E., Dichgans, M., Brüning, R., Gasser, T., Bötzel, K. 2001. Intrafamilial variability in fragile X–associated tremor/ataxia syndrome. Gene Ther 41: 5–12.

    Google Scholar 

  • Pieretti, M., Zhang, F., Fu, Y., Warren, S. T., Oostra, B. A., Caskey, C. T., Nelson, D. L. 1991. Absence of expression of the FMR–1 gene in fragile X syndrome. Cell (Cambridge) 66: 817–822.

    Article  CAS  Google Scholar 

  • Primerano, B., Tassone, F., Hagerman, R. J., Hagerman, P. J., Amaldi, F., Bagni, C. 2002. Reduced FMR1 mRNA translation efficiency in fragile X patients with premutations. RNA 8: 1482–1488.

    PubMed  CAS  Google Scholar 

  • Rodriguez-Revenga, L., Madrigal, I., Pagonabarraga, J., Xunclà, M., Badenas, C., Kulisevsky, J., Gomez, B., Milà, M. 2009. Penetrance of FMR1 premutation associated pathologies in fragile X syndrome families. Eur J Hum Genet 17(10): 1359–1362.

    Article  PubMed  CAS  Google Scholar 

  • Rousseau, F., Rouillard, P., Morel, M. L., Khandjian, E. W., Morgan, K. 1995. Prevalence of carriers of premutation-size alleles of the FMR1 gene – and implications for the population genetics of the fragile X syndrome. Am J Hum Genet 57: 1006.

    PubMed  CAS  Google Scholar 

  • Sellier, C., Rau, F., Liu, Y., Tassone, F., Hukema, R. K., Gattoni, R., Schneider, A., Richard, S., Willemsen, R., Elliott, D. J., Hagerman, P. J., Charlet-Berguerand, N. 2010. Sam68 sequestration and partial loss of function are associated with splicing alterations in FXTAS patients. EMBO J.

    Google Scholar 

  • Sittler, A., Devys, D., Weber, C., Mandel, J. L. 1996. Alternative splicing of exon 14 determines nuclear or cytoplasmic localisation of fmr1 protein isoforms. Hum Mol Genet 5: 95–102.

    Article  CAS  Google Scholar 

  • Soontarapornchai, K., Maselli, R., Fenton-Farrell, G., Tassone, F., Hagerman, P. J., Hessl, D., Hagerman, R. J. 2008. Abnormal nerve conduction features in fragile X premutation carriers. Arch Neurol 65: 495.

    Article  PubMed  Google Scholar 

  • Taneja, K. L. 1995. Foci of trinucleotide repeat transcripts in nuclei of myotonic dystrophy cells and tissues. J Cell Biol 128: 995–1002.

    Article  PubMed  CAS  Google Scholar 

  • Tassone, F., Hagerman, R. J., Loesch, D. Z., Lachiewicz, A., Taylor, A. K., Hagerman, P. J. 2000a. Fragile X males with unmethylated, full mutation trinucleotide repeat expansions have elevated levels of FMR1 messenger RNA. Am J Med Genet 94: 232–236.

    Article  PubMed  CAS  Google Scholar 

  • Tassone, F., Hagerman, R. J., Taylor, A. K., Gane, L. W., Godfrey, T. E., Hagerman, P. J. 2000b. Elevated levels of FMR1 mRNA in carrier males: a new mechanism of involvement in the fragile-X syndrome. Am J Hum Genet 66: 6–15.

    Article  PubMed  CAS  Google Scholar 

  • Tassone, F., Hagerman, R. J., Chamberlain, W. D., Hagerman, P. J. 2000c. Transcription of the FMR1 gene in individuals with fragile X syndrome. Am J Med Genet (Semin Med Genet) 97: 195–203.

    Article  CAS  Google Scholar 

  • Tassone, F., Hagerman, R. J., Garcia-Arocena, D., Khandjian, E. W., Greco, C. M., Hagerman, P. J. 2004a. Intranuclear inclusions in neural cells with premutation alleles in fragile X associated tremor/ataxia syndrome. J Med Genet 41: e43.

    Article  PubMed  CAS  Google Scholar 

  • Tassone, F., Iwahashi, C., Hagerman, P. J. 2004b. FMR1 RNA within the intranuclear inclusions of fragile X-associated tremor/ataxia syndrome (FXTAS). RNA Biol 1: 103–105.

    Article  PubMed  CAS  Google Scholar 

  • Tassone, F., Adams, J., Berry-Kravis, E. M., Cohen, S. S., Brusco, A., Leehey, M. A., Li, L., Hagerman, R. J., Hagerman, P. J. 2007a. CGG repeat length correlates with age of onset of motor signs of the fragile X-associated tremor/ataxia syndrome (FXTAS). Am J Med Genet B Neuropsychiatr Genet 144: 566–569.

    Google Scholar 

  • Tassone, F., Beilina, A., Carosi, C., Albertosi, S., Bagni, C., Li, L., Glover, K., Bentley, D., Hagerman, P. J. 2007b. Elevated FMR1 mRNA in premutation carriers is due to increased transcription. RNA 13: 555–562.

    Article  PubMed  CAS  Google Scholar 

  • Toledano-Alhadef, H., Basel-Vanagaite, L., Magal, N., Davidov, B., Ehrlich, S., Drasinover, V., Taub, E., Halpern, G. J., Ginott, N., Shohat, M. 2001. Fragile-X carrier screening and the prevalence of premutation and full-mutation carriers in Israel. Am J Hum Genet 69: 351–360.

    Article  PubMed  CAS  Google Scholar 

  • Turner, G., Webb, T., Wake, S., Robinson, H. 1996. Prevalence of fragile X syndrome. Am J Med Genet 64: 196–197.

    Article  PubMed  CAS  Google Scholar 

  • Tzeng, C. C., Tsai, L. P., Hwu, W. L., Lin, S. J., Chao, M. C., Jong, Y. J., Chu, S. Y., Chao, W. C., Lu, C. L. 2005. Prevalence of the FMR1 mutation in Taiwan assessed by large-scale screening of newborn boys and analysis of DXS548-FRAXAC1 haplotype. Am J Med Genet A 133: 37–43.

    Google Scholar 

  • Verheij, C., Bak, C. E., de Graaff, E. 1993. Characterization and localization of the FMR–1 gene product associated with fragile X syndrome. Nature 363: 722–724.

    Article  PubMed  CAS  Google Scholar 

  • Verheij, C., de Graaff, E., Bakker, C. E., Willemsen, R., Willems, P. J., Meijer, N., Galjaard, H., Reuser, A. J., Oostra, B. A., Hoogeveen, A. T. 1995. Characterization of FMR1 proteins isolated from different tissues. Hum Mol Genet 4: 895–901.

    Article  PubMed  CAS  Google Scholar 

  • Verkerk, A. J., Pieretti, M., Sutcliffe, J. S., Fu, Y. H., Kuhl, D. P., Pizzuti, A., Reiner, O., Richards, S., Victoria, M. F., Zhang, F. P. 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.

    Article  PubMed  CAS  Google Scholar 

  • Verkerk, A., de Graaff, E., De Boulle, K., Eichler, E. E., Konecki, D. S., Reyniers, E., Manca, A., Poustka, A., Willems, P. J., Nelson, D. L. 1993. Alternative splicing in the fragile X gene FMR1. Hum Mol Genet 2(4): 399–404.

    Article  PubMed  CAS  Google Scholar 

  • Willemsen, R., Hoogeveen-Westerveld, M., Reis, S., Holstege, J., Severijnen, L., Nieuwenhuizen, I. M., Schrier, M., van Unen, L., Tassone, F., Hoogeveen, A. T. 2003. The FMR1 CGG repeat mouse displays ubiquitin-positive intranuclear neuronal inclusions; implications for the cerebellar tremor/ataxia syndrome. Hum Mol Genet 12: 949.

    Article  PubMed  CAS  Google Scholar 

  • Yu, S., Pritchard, M., Kremer, E., Lynch, M., Nancarrow, J., Baker, E., Holman, K., Mulley, J. C., Warren, S. T., Schlessinger, D. 1991. Fragile X genotype characterized by an unstable region of DNA. Science 252: 1179–1181.

    Article  CAS  Google Scholar 

  • Zhong, N., Yang, W., Dobkin, C., Brown, W. T. 1995. Fragile X gene instability: anchoring AGGs and linked microsatellites. Am J Hum Genet 57: 351.

    PubMed  CAS  Google Scholar 

  • Zhong, N., Ju, W., Pietrofesa, J., Wang, D., Dobkin, C., Brown, W. T. 1996. Fragile xgray-zone alleles: AGG patterns, expansion risks, and associated haplotypes. Am J Med Genet 64: 261–265.

    Article  PubMed  CAS  Google Scholar 

  • Zühlke, C., Budnik, A., Gehlken, U., Dalski, A., Purmann, S., Naumann, M., Schmidt, M., Bürk, K., Schwinger, E. 2004. FMR1 premutation as a rare cause of late onset ataxia: evidence for FXTAS in female carriers. J Neurol 251: 1418–1419.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, CA, USA

    Flora Tassone & Paul J. Hagerman

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  1. Flora Tassone
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  2. Paul J. Hagerman
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Correspondence to Flora Tassone .

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  1. Dept. Biochemistry & Molecular Medicine, University of California, Davis, Davis, 95616, California, USA

    Flora Tassone

  2. Medical Center, Dept. Pediatrics, Rush University, 1725 W. Harrison St., Suite 718, Chicago, 60612, Illinois, USA

    Elizabeth M. Berry-Kravis

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Tassone, F., Hagerman, P.J. (2010). The Molecular Biology of FXTAS. In: Tassone, F., Berry-Kravis, E. (eds) The Fragile X-Associated Tremor Ataxia Syndrome (FXTAS). Springer, New York, NY. https://doi.org/10.1007/978-1-4419-5805-1_6

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