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Gene Review

FRAXA  -  fragile site, folic acid type, rare,...

Homo sapiens

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Disease relevance of FRAXA

  • Molecular diagnosis to exclude the fragile X (FRAXA) syndrome used the direct probe pfxa3, together with a control probe pS8 (DXS296), against PstI restriction digests of DNA [1].
  • Deletions of the IDS gene can include a conserved locus that is tightly linked to FRAXA, suggesting that deletion of nearby genes may contribute to the variable clinical severity noted in Hunter syndrome [2].
  • There is evidence that male subjects with a clinical picture of action tremor, Parkinsonism, and cerebellar ataxia may have Fragile X premutations (FRAXA) [3].
  • Families with mentally retarded males found to be negative for FRAXA and FRAXE mutations are useful in understanding the genetic basis of X-linked mental retardation [4].
  • We analyzed FRAXA and FRAXE triplet repeats in 203 male subjects with Parkinson's disease (PD) and 370 healthy controls [3].

Psychiatry related information on FRAXA


High impact information on FRAXA

  • Acetylated histones are associated with FMR1 in normal but not fragile X-syndrome cells [10].
  • The most common FMR1 mutation is expansion of a CGG repeat tract at the 5' end of FMR1, which leads to cytosine methylation and transcriptional silencing [10].
  • Our results represent the first description of loss of histone acetylation at a specific locus in human disease, and advance understanding of the mechanism of FMR1 transcriptional silencing [10].
  • FRAXA expansion results in fragile X syndrome due to down regulation of expression of the FMR1 gene, which carries the hypermutable CGG repeat in the 5' untranslated portion of its first exon [5].
  • A 5-kilobase EcoRI fragment derived from a cosmid coincident with the cytogenetic anomaly detects expanded, methylated and unstable sequences in five individuals who exhibit fragile sites in distal Xq; these individuals have normal repeat lengths at both FRAXA and FRAXE [11].

Chemical compound and disease context of FRAXA

  • A further two families had consistent expression of a different folate sensitive fragile site, FRAXE, close to FRAXA but not associated with fragile X syndrome and not detectable with the pfxa3 probe [12].

Biological context of FRAXA

  • This situation is similar to that seen at the FRAXA locus and is another example in which a trinucleotide repeat expansion is associated with a human genetic disorder [13].
  • Three folate-sensitive fragile sites, termed FRAXA, FRAXE and FRAXF, have been identified on the distal end of chromosome Xq [11].
  • Our results suggest that the threshold of repeat length for abnormal methylation and fragile-site expression may be smaller at FRAXE than at FRAXA [14].
  • The locus DXS304 is closely linked to FRAXA, giving a peak lod score of 5.86 at a corresponding recombination fraction of .00 [15].
  • To define more extensively this altered region of DNA replication, as well as to extend these studies to female cells containing premutant and mutant alleles, study of the replication timing properties of a >2-Mb zone in the FRAXA region (Xq27.3-q28) was undertaken by using a FISH technique [16].

Anatomical context of FRAXA

  • The apparent enrichment for breakpoints lying within the Hprt-DXHX254E region is discussed in relation to both the nature of the embryonic stem cell fusions and the presence of the Fmr1 gene associated with FRAXA in man within this span [17].
  • We have recently reported results of DNA replication analysis of three X-linked loci (FRAXA, F8C and XIST) on the X chromosomes in male and female fibroblasts using fluorescence in situ hybridization (FISH) (1) [18].
  • Pathological studies from the brains of patients and from Fmr1 knockout mice show abnormal dendritic spines implicating FMRP in synapse formation and function [19].
  • Physical mapping of new DNA probes near the fragile X mutation (FRAXA) by using a panel of cell lines [20].
  • We report the validation and use of a cell hybrid panel which allowed us a rapid physical localization of new DNA probes in the vicinity of the fragile-X locus (FRAXA) [21].

Associations of FRAXA with chemical compounds

  • We have developed an assay which allows simultaneous amplification of the triplet repeat sequences at the FRAXA and FRAXE loci by polymerase chain reaction, and detection of the products on non-denaturing gels stained with ethidium bromide [22].
  • Treatment with acetyl-L-carnitine (ALC), a compound that reduces the in vitro expression of the FRAXA fragile site without affecting DNA methylation, caused an increase of H3 and H4 acetylation [23].
  • By using the bisulfite protocol of the genomic sequencing method, we have determined the methylation patterns in this region on single chromosomes of healthy individuals and of selected premutation carriers and FRAXA patients [24].
  • The overall evaluation of the in situ and genetic data reported suggest that the CDR locus 1) is located at the upper boundary of the FRAXA site; 2) is distal to DXS51 and proximal to DXS 389; and 3) segregates in a close linkage association with the loci DXS98 and DXS105 and, to a lesser extent, with the locus for MBS [25].
  • Given this observation and knowing that the open reading frame of the mutated FMR1 gene is intact, we decided to investigate whether its activity could be restored in vitro by inducing DNA demethylation with 5-azadeoxycytidine (5-azadC) in fragile X patients' lymphoblastoid cells [26].

Regulatory relationships of FRAXA

  • Therefore, it appears that FRAXD occurs very rarely in cultures treated to induce FRAXA since only one positive cell was observed in over 88,000 analyzed [27].

Other interactions of FRAXA

  • It appears that very low frequencies of fra(X)(q27) can be accounted for only in part by the presence of the common fragile site since only one of 9 cases, each with one fra(X)(q27) positive cell, exhibited FRAXD and the others were FRAXA [27].
  • In dealing with patients who are found to have fragile sites, other than FRAXA, FRAXE and possibly FRA11B, considerable reassurance can be given that they are not at increased risk of having children with congenital disease or developing disease themselves because of their fragile sites [28].
  • In contrast to the rare fragile sites, including FRAXA, no repeat motifs, such as trinucleotide repeats, have been identified within FRA3B [29].
  • Premutations of the fragile-X (FRAXA) gene were thought to have no clinical effects until recent reports of an increased incidence of premature ovarian failure in females and a late-onset neurological disorder in males [30].
  • In this study of fragile X fra(X) syndrome families, the DXS105 locus was calculated to be proximal to FRAXA with a maximum lod score of 10.36 at theta = 0.08 [31].

Analytical, diagnostic and therapeutic context of FRAXA


  1. Overlapping submicroscopic deletions in Xq28 in two unrelated boys with developmental disorders: identification of a gene near FRAXE. Gedeon, A.K., Meinänen, M., Adès, L.C., Kääriäinen, H., Gécz, J., Baker, E., Sutherland, G.R., Mulley, J.C. Am. J. Hum. Genet. (1995) [Pubmed]
  2. Frequent deletions at Xq28 indicate genetic heterogeneity in Hunter syndrome. Wilson, P.J., Suthers, G.K., Callen, D.F., Baker, E., Nelson, P.V., Cooper, A., Wraith, J.E., Sutherland, G.R., Morris, C.P., Hopwood, J.J. Hum. Genet. (1991) [Pubmed]
  3. FRAXE intermediate alleles are associated with Parkinson's disease. Annesi, G., Nicoletti, G., Tarantino, P., Cutuli, N., Annesi, F., Marco, E.V., Zappia, M., Morgante, L., Arabia, G., Pugliese, P., Condino, F., Carrideo, S., Civitelli, D., Caracciolo, M., Romeo, N., Spadafora, P., Candiano, I.C., Quattrone, A. Neurosci. Lett. (2004) [Pubmed]
  4. Mapping to distal Xq28 of nonspecific X-linked mental retardation MRX72: linkage analysis and clinical findings in a three-generation Sardinian family. Russo, S., Cogliati, F., Cavalleri, F., Cassitto, M.G., Giglioli, R., Toniolo, D., Casari, G., Larizza, L. Am. J. Med. Genet. (2000) [Pubmed]
  5. Identification of FMR2, a novel gene associated with the FRAXE CCG repeat and CpG island. Gu, Y., Shen, Y., Gibbs, R.A., Nelson, D.L. Nat. Genet. (1996) [Pubmed]
  6. FRAXA and FRAXE: the results of a five year survey. Youings, S.A., Murray, A., Dennis, N., Ennis, S., Lewis, C., McKechnie, N., Pound, M., Sharrock, A., Jacobs, P. J. Med. Genet. (2000) [Pubmed]
  7. Longitudinal changes in cognitive and adaptive behavior scores in children and adolescents with the fragile X mutation or autism. Fisch, G.S., Simensen, R.J., Schroer, R.J. Journal of autism and developmental disorders. (2002) [Pubmed]
  8. Deletion of FMR1 in Purkinje cells enhances parallel fiber LTD, enlarges spines, and attenuates cerebellar eyelid conditioning in Fragile X syndrome. Koekkoek, S.K., Yamaguchi, K., Milojkovic, B.A., Dortland, B.R., Ruigrok, T.J., Maex, R., De Graaf, W., Smit, A.E., VanderWerf, F., Bakker, C.E., Willemsen, R., Ikeda, T., Kakizawa, S., Onodera, K., Nelson, D.L., Mientjes, E., Joosten, M., De Schutter, E., Oostra, B.A., Ito, M., De Zeeuw, C.I. Neuron (2005) [Pubmed]
  9. Behavioral and neuroanatomical characterization of the Fmr1 knockout mouse. Mineur, Y.S., Sluyter, F., de Wit, S., Oostra, B.A., Crusio, W.E. Hippocampus. (2002) [Pubmed]
  10. Acetylated histones are associated with FMR1 in normal but not fragile X-syndrome cells. Coffee, B., Zhang, F., Warren, S.T., Reines, D. Nat. Genet. (1999) [Pubmed]
  11. Isolation of a GCC repeat showing expansion in FRAXF, a fragile site distal to FRAXA and FRAXE. Parrish, J.E., Oostra, B.A., Verkerk, A.J., Richards, C.S., Reynolds, J., Spikes, A.S., Shaffer, L.G., Nelson, D.L. Nat. Genet. (1994) [Pubmed]
  12. Experience with direct molecular diagnosis of fragile X. Mulley, J.C., Yu, S., Gedeon, A.K., Donnelly, A., Turner, G., Loesch, D., Chapman, C.J., Gardner, R.J., Richards, R.I., Sutherland, G.R. J. Med. Genet. (1992) [Pubmed]
  13. Trinucleotide repeat amplification and hypermethylation of a CpG island in FRAXE mental retardation. Knight, S.J., Flannery, A.V., Hirst, M.C., Campbell, L., Christodoulou, Z., Phelps, S.R., Pointon, J., Middleton-Price, H.R., Barnicoat, A., Pembrey, M.E. Cell (1993) [Pubmed]
  14. 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. Biancalana, V., Taine, L., Bouix, J.C., Finck, S., Chauvin, A., De Verneuil, H., Knight, S.J., Stoll, C., Lacombe, D., Mandel, J.L. Am. J. Hum. Genet. (1996) [Pubmed]
  15. Linkage analysis of families with fragile-X mental retardation, using a novel RFLP marker (DXS 304). Dahl, N., Goonewardena, P., Malmgren, H., Gustavson, K.H., Holmgren, G., Seemanova, E., Annerén, G., Flood, A., Pettersson, U. Am. J. Hum. Genet. (1989) [Pubmed]
  16. Large domains of apparent delayed replication timing associated with triplet repeat expansion at FRAXA and FRAXE. Subramanian, P.S., Nelson, D.L., Chinault, A.C. Am. J. Hum. Genet. (1996) [Pubmed]
  17. A panel of deleted mouse X chromosome somatic cell hybrids derived from the embryonic stem cell line HD3 shows preferential breakage in the Hprt-DXHX254E region. Arnaud, D., Mattei, M.G., Avner, P. Genomics (1993) [Pubmed]
  18. The XIST locus replicates late on the active X, and earlier on the inactive X based on FISH DNA replication analysis of somatic cell hybrids. Torchia, B.S., Migeon, B.R. Somat. Cell Mol. Genet. (1995) [Pubmed]
  19. A decade of molecular studies of fragile X syndrome. O'Donnell, W.T., Warren, S.T. Annu. Rev. Neurosci. (2002) [Pubmed]
  20. Physical mapping of new DNA probes near the fragile X mutation (FRAXA) by using a panel of cell lines. Suthers, G.K., Hyland, V.J., Callen, D.F., Oberle, I., Rocchi, M., Thomas, N.S., Morris, C.P., Schwartz, C.E., Schmidt, M., Ropers, H.H. Am. J. Hum. Genet. (1990) [Pubmed]
  21. Four chromosomal breakpoints and four new probes mark out a 10-cM region encompassing the fragile-X locus (FRAXA). Rousseau, F., Vincent, A., Rivella, S., Heitz, D., Triboli, C., Maestrini, E., Warren, S.T., Suthers, G.K., Goodfellow, P., Mandel, J.L. Am. J. Hum. Genet. (1991) [Pubmed]
  22. A rapid, non-radioactive screening test for fragile X mutations at the FRAXA and FRAXE loci. Wang, Q., Green, E., Bobrow, M., Mathew, C.G. J. Med. Genet. (1995) [Pubmed]
  23. Differential epigenetic modifications in the FMR1 gene of the fragile X syndrome after reactivating pharmacological treatments. Tabolacci, E., Pietrobono, R., Moscato, U., Oostra, B.A., Chiurazzi, P., Neri, G. Eur. J. Hum. Genet. (2005) [Pubmed]
  24. Methylation mosaicism of 5'-(CGG)(n)-3' repeats in fragile X, premutation and normal individuals. Genç, B., Müller-Hartmann, H., Zeschnigk, M., Deissler, H., Schmitz, B., Majewski, F., von Gontard, A., Doerfler, W. Nucleic Acids Res. (2000) [Pubmed]
  25. Physical and genetic mapping of the CDR gene with particular reference to its position with respect to the FRAXA site. Siniscalco, M., Oberlé, I., Melis, P., Alhadeff, B., Murray, J., Filippi, G., Mattioni, T., Chen, Y.T., Furneaux, H., Old, L.J. Am. J. Med. Genet. (1991) [Pubmed]
  26. In vitro reactivation of the FMR1 gene involved in fragile X syndrome. Chiurazzi, P., Pomponi, M.G., Willemsen, R., Oostra, B.A., Neri, G. Hum. Mol. Genet. (1998) [Pubmed]
  27. Fra(X)(q27.2), the common fragile site, observed in only one of 760 cases studied for the fragile X syndrome. Jenkins, E.C., Genovese, M.J., Duncan, C.J., Gu, H., Stark-Houck, S.L., Lele, K., Li, S.Y., Krawczun, M.S. Am. J. Med. Genet. (1992) [Pubmed]
  28. The clinical significance of fragile sites on human chromosomes. Sutherland, G.R., Baker, E. Clin. Genet. (2000) [Pubmed]
  29. Replication of a common fragile site, FRA3B, occurs late in S phase and is delayed further upon induction: implications for the mechanism of fragile site induction. Le Beau, M.M., Rassool, F.V., Neilly, M.E., Espinosa, R., Glover, T.W., Smith, D.I., McKeithan, T.W. Hum. Mol. Genet. (1998) [Pubmed]
  30. Observation of an excess of fragile-X premutations in a population of males referred with spinocerebellar ataxia. Macpherson, J., Waghorn, A., Hammans, S., Jacobs, P. Hum. Genet. (2003) [Pubmed]
  31. Linkage relationships between DXS105, DXS98, and other polymorphic DNA markers flanking the fragile X locus. Carpenter, N.J., Thibodeau, S.N., Brown, W.T. Am. J. Med. Genet. (1991) [Pubmed]
  32. A simple multiplex FRAXA, FRAXE, and FRAXF PCR assay convenient for wide screening programs. Strelnikov, V., Nemtsova, M., Chesnokova, G., Kuleshov, N., Zaletayev, D. Hum. Mutat. (1999) [Pubmed]
  33. FRAXA locus in fragile X diagnosis: family studies, prenatal diagnosis, and diagnosis of sporadic cases of mental retardation. von Koskull, H., Gahmberg, N., Salonen, R., Salo, A., Peippo, M. Am. J. Med. Genet. (1994) [Pubmed]
  34. MECP2 mutations or polymorphisms in mentally retarded boys: diagnostic implications. Bourdon, V., Philippe, C., Martin, D., Verloès, A., Grandemenge, A., Jonveaux, P. Mol. Diagn. (2003) [Pubmed]
  35. The influence of expanded unmethylated alleles for FRAXA/FRAXE loci in the intellectual performance among Brazilian mentally impaired males. Barros Santos, C., Gonçalves Pimentel, M.M. Int. J. Mol. Med. (2003) [Pubmed]
  36. Non-invasive screening of fragile X syndrome A using urine and hair roots. Suwa, K., Momoi, M.Y. Brain Dev. (2004) [Pubmed]
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