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27 - Role of microRNA pathway in Fragile X mental retardation

from V - MicroRNAs in disease biology

Published online by Cambridge University Press:  22 August 2009

By
Keith Szulwach  and
Peng Jin
Edited by
Krishnarao Appasani
Foreword by
Sidney Altman  and
Victor R. Ambros
Keith Szulwach
Affiliation:
Department of Human Genetics Emory University School of Medicine 615 Michael Street, Room 325.1 Atlanta, GA 30322 USA
Peng Jin
Affiliation:
Department of Human Genetics Emory University School of Medicine 615 Michael Street, Room 325.1 Atlanta, GA 30322 USA
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Summary

Introduction

Loss of the Fragile X Mental Retardation Protein (FMRP) has been identified as the major cause of Fragile X syndrome, one of the most common forms of inherited mental retardation. FMRP's RNA binding character has implicated it in translational regulation. Recently, FMRP has also been linked to the microRNA pathway that is involved in translational suppression. Current work on Fragile X syndrome strives to determine the functional role of FMRP in translational suppression of associated mRNA targets and how components of the microRNA pathway may help to mediate this function.

Clinical phenotypes of Fragile X syndrome

Fragile X syndrome is one of the most common forms of inherited mental retardation with an estimated prevalence of about 1 in 4000 males and 1 in 8000 females. The syndrome is transmitted as an X-linked dominant trait with reduced penetrance (80% in males and 30% in females). The clinical presentations of Fragile X syndrome include mild to severe mental retardation, with IQ between 20 and 70, mildly abnormal facial features of a prominent jaw and large ears, mainly in males, and macroorchidism in post-pubescent males (Crawford et al., 2001; Terracciano et al., 2005). Many patients also display subtle connective tissue abnormalities. Behaviorally, affected males tend to exhibit hyperactivity, social anxiety, preservative speech and language, tactile defensiveness, and hand biting (Crawford et al., 2001; Terracciano et al., 2005).

Type
Chapter
Information
MicroRNAs
From Basic Science to Disease Biology
 , pp. 363 - 371
Publisher: Cambridge University Press
Print publication year: 2007

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References

Ashley, C. T. Jr., Wilkinson, K. D., Reines, D. and Warren, S. T. (1993). FMR1 protein: conserved RNP family domains and selective RNA binding. Science, 262, 563–566.CrossRefGoogle Scholar
Caudy, A. A., Myers, M., Hannon, G. J. and Hammond, S. M. (2002). Fragile X-related protein and VIG associate with the RNA interference machinery. Genes & Development, 16, 2491–2496.CrossRefGoogle Scholar
Ceman, S., O'Donnell, W. T., Reed, M.et al. (2003). Phosphorylation influences the translation state of FMRP-associated polyribosomes. Human Molecular Genetics, 12, 3295–3305.CrossRefGoogle Scholar
Crawford, D. C., Acuna, J. M. & Sherman, S. L. (2001). FMR1 and the fragile X syndrome: human genome epidemiology review. Genetics in Medicine, 3, 359–371.CrossRefGoogle Scholar
Darnell, J. C., Jensen, K. B., Jin, P.et al. (2001). Fragile X mental retardation protein targets G quartet mRNAs important for neuronal function. Cell, 107, 489–499.CrossRefGoogle Scholar
Darnell, J. C., Warren, S. T. and Darnell, R. B. (2004). The fragile X mental retardation protein, FMRP, recognizes G-quartets. Mental Retardation and Developmental Disabilities Research Reviews, 10, 49–52.CrossRefGoogle Scholar
Darnell, J. C., Fraser, C. E., Mostovetsky, O.et al. (2005). Kissing complex RNAs mediate interaction between the Fragile-X mental retardation protein KH2 domain and brain polyribosomes. Genes & Development, 19, 903–918.CrossRefGoogle Scholar
Devys, D., Lutz, Y., Rouyer, N., Bellocq, J. P. and Mandel, J. L. (1993). The FMR-1 protein is cytoplasmic, most abundant in neurons and appears normal in carriers of a fragile X premutation. Nature Genetics, 4, 335–340.CrossRefGoogle Scholar
Feng, Y., Absher, D., Eberhart, D. E.et al. (1997a). FMRP associates with polyribosomes as an mRNP, and the I304 N mutation of severe fragile X syndrome abolishes this association. Molecular Cell, 1, 109–118.Google Scholar
Feng, Y., Gutekunst, C. A., Eberhart, D. E.et al. (1997b). Fragile X mental retardation protein: nucleocytoplasmic shuttling and association with somatodendritic ribosomes. Journal of Neuroscience, 17, 1539–1547.Google Scholar
Handa, V., Saha, T. and Usdin, K. (2003). The fragile X syndrome repeats form RNA hairpins that do not activate the interferon-inducible protein kinase, PKR, but are cut by Dicer. Nucleic Acids Research, 31, 6243–6248.CrossRefGoogle Scholar
Huber, K. M., Kayser, M. S. and Bear, M. F. (2000). Role for rapid dendritic protein synthesis in hippocampal mGluR-dependent long-term depression. Science, 288, 1254–1257.CrossRefGoogle Scholar
Huber, K. M., Gallagher, S. M., Warren, S. T. and Bear, M. F. (2002). Altered synaptic plasticity in a mouse model of fragile X mental retardation. Proceedings of the National Academy of Sciences USA, 99, 7746–7750.CrossRefGoogle Scholar
Ishizuka, A., Siomi, M. C. and Siomi, H. (2002). A Drosophila fragile X protein interacts with components of RNAi and ribosomal proteins. Genes & Development, 16, 2497–2508.CrossRefGoogle Scholar
Jin, P., Zarnescu, D. C., Ceman, S.et al. (2004). Biochemical and genetic interaction between the fragile X mental retardation protein and the microRNA pathway. Nature Neuroscience, 7, 113–117.CrossRefGoogle Scholar
Laggerbauer, B., Ostareck, D., Keidel, E. M., Ostareck-Lederer, A. and Fischer, U. (2001). Evidence that fragile X mental retardation protein is a negative regulator of translation. Human Molecular Genetics, 10, 329–338.CrossRefGoogle Scholar
Li, Z., Zhang, Y., Ku, L.et al. (2001). The fragile X mental retardation protein inhibits translation via interacting with mRNA. Nucleic Acids Research, 29, 2276–2283.CrossRefGoogle Scholar
Lu, R., Wang, H., Liang, Z.et al. (2004). The fragile X protein controls microtubule-associated protein 1B translation and microtubule stability in brain neuron development. Proceedings of the National Academy of Sciences USA, 101, 15 201–15 206.Google Scholar
Lugli, G., Larson, J., Martone, M. E., Jones, Y. and Smalheiser, N. R. (2005). Dicer and eIF2c are enriched at postsynaptic densities in adult mouse brain and are modified by neuronal activity in a calpain-dependent manner. Journal of Neurochemistry, 94, 896–905.CrossRefGoogle Scholar
Okamura, K., Ishizuka, A., Siomi, H. and Siomi, M. C. (2004). Distinct roles for Argonaute proteins in small RNA-directed RNA cleavage pathways. Genes & Development, 18, 1655–1666.CrossRefGoogle Scholar
Ramos, A., Hollingworth, D. and Pastore, A. (2003). G-quartet-dependent recognition between the FMRP RGG box and RNA. RNA, 9, 1198–1207.CrossRefGoogle Scholar
Schaeffer, C., Bardoni, B., Mandel, J. L.et al. (2001). The fragile X mental retardation protein binds specifically to its mRNA via a purine quartet motif. European Molecular Biology Organization Journal, 20, 4803–4813.CrossRefGoogle Scholar
Siomi, M. C., Zhang, Y., Siomi, H. & Dreyfuss, G. (1996). Specific sequences in the fragile X syndrome protein FMR1 and the FXR proteins mediate their binding to 60 S ribosomal subunits and the interactions among them. Molecular and Cellular Biology, 16, 3825–3832.CrossRefGoogle Scholar
Stetler, A., Winograd, C., Sayegh, J.et al. (2006). Identification and characterization of the methyl arginines in the fragile X mental retardation protein Fmrp. Human Molecular Genetics, 15, 87–96.CrossRefGoogle Scholar
Terracciano, A., Chiurazzi, P. & Neri, G. (2005). Fragile X syndrome. American Journal of Medical Genetics. Part C, Seminars in Medical Genetics, 137, 32–37.CrossRefGoogle Scholar
Xu, K., Bogert, B. A., Li, W.et al. (2004). The fragile X-related gene affects the crawling behavior of Drosophila larvae by regulating the mRNA level of the DEG/ENaC protein pickpocket1. Current Biology, 14, 1025–1034.CrossRefGoogle Scholar
Zhang, Y., O'Connor, J. P., Siomi, M. C.et al. (1995). The fragile X mental retardation syndrome protein interacts with novel homologs FXR1 and FXR2. European Molecular Biology Organization Journal, 14, 5358–5366.Google Scholar
Zhang, Y. Q., Bailey, A. M., Matthies, H. J.et al. (2001). Drosophila fragile X-related gene regulates the MAP1B homolog Futsch to control synaptic structure and function. Cell, 107, 591–603.CrossRefGoogle Scholar

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