Abstract
The first triplet-repeat mutation to be reported was the large d(CGG) repeat expansion found in individuals with Fragile X syndrome (Verkerk et al. 1991). Significant attention has been paid to this common disease, the dynamics of its d(CGG) repeat, and the function of its associated gene, FMR1 (Bagni and Greenough 2005). However, two other folate-sensitive fragile sites in the region have received much less attention since they were found to be distinct from the sequence affected in Fragile X syndrome. These sites, FRAXE and FRAXF are reviewed here. FRAXE expansion results in a mild learning deficit, can lead to more severe mental retardation, and has been associated with other mental disorders. FRAXF is apparently benign when expanded despite affecting at least one nearby gene. Interestingly, each of the fragile site loci contains a d(CGG) or d(CCG) repeat that is expressed in the 5′ untranslated portion of a neuronally expressed gene. Each expanded repeat sequence exhibits similar properties of instability, methylation and extinction of gene expression resulting in a loss of function of the associated genes. Advances in understanding the role of the repeat expansions in FRAXE and FRAXF and associated genomics and models are presented.
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References
Bagni C, Greenough WT (2005) From mRNP trafficking to spine dysmorphogenesis: the roots of fragile X syndrome. Nat Rev Neurosci 6:376–387
Barnicoat A, Wang Q, Turk J, Green E, Mathew CG, Flynn G, Buckle V, Hirst M, Davies K, Bobrow M (1997) Clinical, cytogenetic, and molecular analysis of three families with FRAXE. J Med Genet 34:13–17
Bear MF, Huber KM, Warren ST (2004) The mGluR theory of fragile X mental retardation. Trends Neurosci 27:370–377
Biancalana V, Taine L, Bouix JC, Finck S, Chauvin A, De Verneuil H, Knight SJ, Stoll C, Lacombe D, Mandel JL (1996) Expansion and methylation status at FRAXE can be detected on EcoRI blots used for FRAXA diagnosis: analysis of four FRAXE families with mild mental retardation in males. Am J Hum Genet 59:847–854
Bontekoe CJ, McIlwain KL, Nieuwenhuizen IM, Yuva-Paylor LA, Nellis A, Willemsen R, Fang Z, Kirkpatrick L, Bakker CE, McAninch R, Cheng NC, Merriweather M, Hoogeveen AT, Nelson D, Paylor R, Oostra BA (2002) Knockout mouse model for Fxr2: a model for mental retardation. Hum Mol Genet 11:487–498
Carbonell P, Lopez I, Gabarron J, Bernabe MJ, Lucas JM, Guitart M, Gabau E, Glover G (1996) FRAXE mutation analysis in three Spanish families. Am J Med Genet 64:434–440
Chakrabarti L, Bristulf J, Foss GS, Davies KE (1998) Expression of the murine homologue of FMR2 in mouse brain and during development. Hum Mol Genet 7:441–448
Chakrabarti L, Knight SJ, Flannery AV, Davies KE (1996) A candidate gene for mild mental handicap at the FRAXE fragile site. Hum Mol Genet 5:275–282
Crawford DC, Meadows KL, Newman JL, Taft LF, Pettay DL, Gold LB, Hersey SJ, Hinkle EF, Stanfield ML, Holmgreen P, Yeargin-Allsopp M, Boyle C, Sherman SL (1999) Prevalence and phenotype consequence of FRAXA and FRAXE alleles in a large, ethnically diverse, special education-needs population. Am J Hum Genet 64:495–507
Eichler EE, Kunst CB, Lugenbeel KA, Ryder OA, Davison D, Warren ST, Nelson DL (1995) Evolution of the cryptic FMR1 CGG repeat. Nature Genet 11:301–308
Flynn GA, Hirst MC, Knight SJ, Macpherson JN, Barber JC, Flannery AV, Davies KE, Buckle VJ (1993) Identification of the FRAXE fragile site in two families ascertained for X linked mental retardation. J Med Genet 30:97–100
Fu YH, Kuhl DP, Pizzuti A, Pieretti M, Sutcliffe JS, Richards S, Verkerk AJ, Holden JJ, Fenwick RG Jr, Warren ST, Oostra BA, Nelson DL, Caskey CT (1991) Variation of the CGG repeat at the fragile X site results in genetic instability: resolution of the Sherman paradox. Cell 67:1047–1058
Gecz J (2000a) FMR3 is a novel gene associated with FRAXE CpG island and transcriptionally silent in FRAXE full mutations. J Med Genet 37:782–784
Gecz J (2000b) The FMR2 gene, FRAXE and non-specific X-linked mental retardation: clinical and molecular aspects. Ann Hum Genet 64:95–106
Gecz J, Gedeon AK, Sutherland GR, Mulley JC (1996) Identification of the gene FMR2, associated with FRAXE mental retardation. Nat Genet 13:105–108
Gecz J, Mulley JC (1999) Characterisation and expression of a large, 13.7 kb FMR2 isoform. Eur J Hum Genet 7:157–162
Gu Y, McIlwain KL, Weeber EJ, Yamagata T, Xu B, Antalffy BA, Reyes C, Yuva-Paylor L, Armstrong D, Zoghbi H, Sweatt JD, Paylor R, Nelson DL (2002) Impaired conditioned fear and enhanced long-term potentiation in Fmr2 knock-out mice. J Neurosci 22:2753–2763
Gu Y, Nelson DL (2003) FMR2 function: insight from a mouse knockout model. Cytogenet Genome Res 100:129–139
Gu Y, Shen Y, Gibbs RA, Nelson DL (1996) Identification of FMR2, a novel gene associated with the FRAXE CCG repeat and CpG island. Nat Genet 13:109–113
Hamel B, Smits AP, de Graaff E, Smeets DF, Schoute F, Eussen BH, Knight SJ, Davies KE, Assman-Hulsmans CF, Oostra BA (1994) Segregation of FRAXE in a large family: clinical, psychometric, cytogenetic, and molecular data. Am J Hum Genet 55:923–931
Hillman MA Gecz J (2001) Fragile XE-associated familial mental retardation protein 2 (FMR2) acts as a potent transcription activator. J Hum Genet 46:251–259
Hirst MC, Barnicoat A, Flynn G, Wang Q, Daker M, Buckle VJ, Davies KE, Bobrow M (1993) The identification of a third fragile site, FRAXF, in Xq27–q28 distal to both FRAXA and FRAXE. Hum Mol Genet 2:197–200
Holden JJ, Julien-Inalsingh C, Chalifoux M, Wing M, Scott E, Fidler K, Swift I, Maidment B, Knight SJ, Davies KE, White BN (1996a) Trinucleotide repeat expansion in the FRAXE locus is not common among institutionalized individuals with non-specific developmental disabilities. Am J Med Genet 64:420–423
Holden JJ, Walker M, Chalifoux M, White BN (1996b) Trinucleotide repeats at the FRAXF locus: frequency and distribution in the general population. Am J Med Genet 64:424–427
Kallinen J, Heinonen S, Mannermaa A, Ryynanen M (2000) Prenatal diagnosis of fragile X syndrome and the risk of expansion of a premutation. Clin Genet 58:111–115
Knight S, Ritchie RJ, Chakrabarti L, Cross G, Taylor GR, Mueller RF, Hurst J, Paterson J, Yates JR, Dow DJ, Davies KE (1996) A study of FRAXE in mentally retarded individuals referred for fragile X syndrome (FRAXA) testing in the United Kingdom. Am J Hum Genet 58:906–913
Knight SJ, Flannery AV, Hirst MC, Campbell L, Christodoulou Z, Phelps SR, Pointon J, Middleton-Price HR, Barnicoat A, Pembrey ME, Holland J, Oostra BA, Bobrow M, Davies KE (1993) Trinucleotide repeat amplification and hypermethylation of a CpG island in FRAXE mental retardation. Cell 74:127–134
Knight SJ, Voelckel MA, Hirst MC, Flannery AV, Moncla A, Davies KE (1994) Triplet repeat expansion at the FRAXE locus and X-linked mild mental handicap. Am J Hum Genet 55:81–86
Kooy RF (2003) Of mice and the fragile X syndrome. Trends Genet 19:148–154
Kremer EJ, Pritchard M, Lynch M, Yu S, Holman K, Baker E, Warren ST, Schlessinger D, Sutherland GR, Richards RI (1991) Mapping of DNA instability at the fragile X to a trinucleotide repeat sequence p(CCG)n. Science 252:1711–1714
Lo Nigro C, Faravelli F, Cavani S, Perroni L, Novello P, Vitali M, Bricarelli FD, Grasso M (2000) FRAXE mutation in a mentally retarded subject and in his phenotypically normal twin brother. Eur J Hum Genet 8:157–162
Lubs H (1969) A marker X chromosome. Am J Hum Genet 21:231–244
Maurer MH, Grunewald S, Gassler N, Rossner M, Propst F, Wurz R, Weber D, Kuner T, Kuschinsky W, Schneider A (2004) Cloning of a novel neuronally expressed orphan G-protein-coupled receptor which is up-regulated by erythropoietin, interacts with microtubule-associated protein 1b and colocalizes with the 5-hydroxytryptamine 2a receptor. J Neurochem 91:1007–1017
Mientjes EJ, Willemsen R, Kirkpatrick LL, Nieuwenhuizen IM, Hoogeveen-Westerveld M, Verweij M, Reis S, Bardoni B, Hoogeveen AT, Oostra BA, Nelson DL (2004) Fxr1 knockout mice show a striated muscle phenotype: implications for Fxr1p function in vivo. Hum Mol Genet 13:1291–1302
Miller WJ, Skinner JA, Foss GS, Davies KE (2000) Localization of the fragile X mental retardation 2 (FMR2) protein in mammalian brain. Eur J Neurosci 12:381–384
Mulley JC, Yu S, Loesch DZ, Hay DA, Donnelly A, Gedeon AK, Carbonell P, Lopez I, Glover G, Gabarron I, Yu PWL, Baker E, Haan EA, Hockey A, Knight SJL, Davis KE, Richards RI, Sutherland GR (1995) FRAXE and mental retardation. J Med Genet 32:162–169
Murgia A, Polli R, Vinanzi C, Salis M, Drigo P, Artifoni L, Zacchello F (1996) Amplification of the Xq28 FRAXE repeats: extreme phenotype variability? Am J Med Genet 64:441–444
Murray A, Youings S, Dennis N, Latsky L, Linehan P, McKechnie N, Macpherson J, Pound M, Jacobs P (1996) Population screening at the FRAXA and FRAXE loci: molecular analyses of boys with learning difficulties and their mothers. Hum Mol Genet 5:727–735
Oberlé I, Rousseau F, Heitz D, Kretz C, Devys D, Hanauer A, Boue J, Bertheas MF, Mandel JL (1991) Instability of a 550-base pair DNA segment and abnormal methylation in fragile X syndrome. Science 252:1097–1102
Parrish JE, Oostra BA, Verkerk AJ, Richards CS, Reynolds J, Spikes AS, Shaffer LG, Nelson DL (1994) Isolation of a GCC repeat showing expansion in FRAXF, a fragile site distal to FRAXA and FRAXE. Nat Genet 8:229–235
Pieretti M, Zhang FP, Fu, YH, Warren ST, Oostra BA, Caskey CT, Nelson DL (1991) Absence of expression of the FMR-1 gene in fragile X syndrome. Cell 66:817–822
Ritchie RJ, Chakrabarti L, Knight SJ, Harding RM, Davies KE (1997) Population genetics of the FRAXE and FRAXF GCC repeats, and a novel CGG repeat, in Xq28. Am J Med Genet 73:463–469
Ritchie RJ, Knight SJ, Hirst MC, Grewal PK, Bobrow M, Cross GS, Davies KE (1994) The cloning of FRAXF: trinucleotide repeat expansion and methylation at a third fragile site in distal Xqter. Hum Mol Genet 3:2115–2121
Russo S, Selicorni A, Bedeschi MF, Natacci F, Viziello P, Fortuna R, Pagani G, Dalpra L, Larizza L (1998) Molecular characterization of FRAXE-positive subjects with mental impairement in two unrelated Italian families. Am J Med Genet 75:304–308
Shaw MA, Chiurazzi P, Romain DR, Neri G, Gecz J (2002) A novel gene, FAM11A, associated with the FRAXF CpG island is transcriptionally silent in FRAXF full mutation. Eur J Hum Genet 10:767–772
Su M, Wisotzkey RG, Newfeld SJ (2001) A screen for modifiers of decapentaplegic mutant phenotypes identifies lilliputian, the only member of the Fragile-X/Burkitt’s Lymphoma family of transcription factors in Drosophila melanogaster. Genetics 157:717–725
Sutherland G, Baker E (1992) Characterization of a new rare fragile site easily confused with the fragile X. Hum Mol Genet 1:111–113
Sutherland GR, Ashforth PLC (1979) X-linked mental retardation with macroorchidism and the fragile site at Xq27 or 28. Hum Genet 48:117–120
Tang A, Neufeld TP, Rubin GM, Muller HA (2001) Transcriptional regulation of cytoskeletal functions and segmentation by a novel maternal pair-rule gene, lilliputian. Development 128:801–813
Verkerk AJ, Pieretti M, Sutcliffe JS, Fu YH, Kuhl DP, Pizzuti A, Reiner O, Richards S, Victoria MF, Zhang FP, Eussen BE, van Ommen GJB, Blonden LAJ, Riggins GJ, Chastain JL, Kunst CB, Galjaard H, Caskey CT, Nelson DL, Oostra BA, Warren ST (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
Wang Q, Gu Y, Ferguson JM, Chen Q, Boatwright S, Gardiner J, Below C, Espinosa J, Nelson DL, Shaffer LG (2003) Cytogenetic analysis of obsessive-compulsive disorder (OCD): identification of a FRAXE fragile site. Am J Med Genet A 118:25–28
Wittwer F, van der Straten A, Keleman K, Dickson BJ, Hafen E (2001) Lilliputian: an AF4/FMR2-related protein that controls cell identity and cell growth. Development 128:791–800
Youings, SA, Murray A, Dennis N, Ennis S, Lewis C, McKechnie N, Pound M, Sharrock, A, Jacobs P (2000) FRAXA and FRAXE: the results of a five year survey. J Med Genet 37:415–421
Yu S, Pritchard M, Kremer E, Lynch M, Nancarrow J, Baker E, Holman K, Mulley JC, Warren ST, Schlessinger D, Sutherland GR, Richards RI (1991) Fragile X genotype characterized by an unstable region of DNA. Science 252:1179–1181
Zhang Y, Oconnor JP, Siomi MC, Srinivasan S, Dutra A, Nussbaum RL, Dreyfuss G (1995) The fragile X mental retardation syndrome protein interacts with novel homologs FXR1 and FXR2. EMBO J 14:5358–5366
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Nelson, D.L., Gu, Y. (2006). The Neglected Fragile X Mutations: FRAXE and FRAXF . In: Fry, M., Usdin, K. (eds) Human Nucleotide Expansion Disorders. Nucleic Acids and Molecular Biology, vol 19. Springer, Berlin, Heidelberg. https://doi.org/10.1007/3-540-33336-3_3
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DOI: https://doi.org/10.1007/3-540-33336-3_3
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