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Gene Review:

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

Homo sapiens

Holden, J.J. et al., Biancalana, V. et al., Allingham-Hawkins, D.J. et al., Ritchie, R.J. et al., Knight, S.J. et al., et al.

Gécz,

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Disease relevance of FRAXE

The expression of FRAXA is associated with the fragile X syndrome, the most prevalent form of inherited mental retardation whilst the expression of FRAXE is associated with a rarer and comparatively milder form of mental handicap [1].
FRAXA, FRAXE, and FRAXF are folate-sensitive fragile sites originally discovered in patients with X-linked mental retardation [2].
FRAXE intermediate alleles are associated with Parkinson's disease [3].

Psychiatry related information on FRAXE

Expansion of a (CGG)n trinucleotide repeat unit at FRAXE, a newly defined fragile site distal to FRAXA, at Xq28, is reported to be associated with mild mental retardation [4].
Trinucleotide repeat expansion in the FRAXE locus is not common among institutionalized individuals with non-specific developmental disabilities [5].
Segregation of FRAXE in a large family: clinical, psychometric, cytogenetic, and molecular data [6].
We report the results of a five year survey of FRAXA and FRAXE mutations among boys aged 5 to 18 with special educational needs (SEN) related to learning disability [7].

High impact information on FRAXE

Trinucleotide repeat amplification and hypermethylation of a CpG island in FRAXE mental retardation [8].
Large domains of apparent delayed replication timing associated with triplet repeat expansion at FRAXA and FRAXE [9].
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 [10].
Our results suggest that the threshold of repeat length for abnormal methylation and fragile-site expression may be smaller at FRAXE than at FRAXA [10].
The data support the hypothesis that FRAXE is either very rare or a benign fragile site that is not associated with any clinical phenotype, similar to the FRAXF and FRA16A sites [4].

Biological context of FRAXE

Investigation of the site of chromosome fragility in these FMR1 mutation negative, fragile X site positive individuals, has identified a second site of fragility, FRAXE [11].
Three fragile sites, FRAXA, FRAXE and FRAXF lie in the Xq27-28 region of the human X chromosome [1].
3. Although FRAXA and FRAXE are indistinguishable by means of conventional cytogenetics, they can now be delineated at the molecular level and provides the basis for a proper diagnosis [12].
We have identified a novel gene, FMR3, originating from the FRAXE CpG island [13].
Normal individuals have 6-25 copies of the GCC repeat, whereas mentally retarded, FRAXE-positive individuals have > 200 copies and also have methylation at the CpG island [8].

Anatomical context of FRAXE

We confirmed that the replication of the fragile-X E site (FRAXE) in human chromosomal band Xq28 occurs at six hours into the eight-hour S phase of normal human fibroblasts [14].

Associations of FRAXE with chemical compounds

Fluorescence in situ hybridisation with cosmid DNA from loci immediately flanking FRAXA and other distal loci have confirmed that cytogenetic fragility in these subjects is the result of expression of a new folate sensitive fragile X site, FRAXE [15].

Other interactions of FRAXE

The identification of a third fragile site, FRAXF, in Xq27--q28 distal to both FRAXA and FRAXE [11].
Expansion of a polymorphic GCC-repeat at the FRAXE locus has been associated with expression of chromosome fragility at this site and cognitive impairment in some individuals previously testing negative for CGG-repeat expansion in the fragile X mental retardation-1 (FMR1) gene [5].
Studies of FRAXA and FRAXE in women with premature ovarian failure [16].

Analytical, diagnostic and therapeutic context of FRAXE

A simple multiplex FRAXA, FRAXE, and FRAXF PCR assay convenient for wide screening programs [2].
These results suggest that FRAXE GCC-repeat expansion is not a common cause of developmental disability in institutionalized persons with mild to profound mental retardation [5].
The original test for the analysis of the CCG expansion at the FRAXE locus involves Southern blot analysis of HindIII digests [10].

References

The cloning of FRAXF: trinucleotide repeat expansion and methylation at a third fragile site in distal Xqter. Ritchie, R.J., Knight, S.J., Hirst, M.C., Grewal, P.K., Bobrow, M., Cross, G.S., Davies, K.E. Hum. Mol. Genet. (1994) [Pubmed]
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]
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]
FRAXE expansion is not a common etiological factor among developmentally delayed males. Allingham-Hawkins, D.J., Ray, P.N. Am. J. Hum. Genet. (1995) [Pubmed]
Trinucleotide repeat expansion in the FRAXE locus is not common among institutionalized individuals with non-specific developmental disabilities. Holden, J.J., Julien-Inalsingh, C., Chalifoux, M., Wing, M., Scott, E., Fidler, K., Swift, I., Maidment, B., Knight, S.J., Davies, K.E., White, B.N. Am. J. Med. Genet. (1996) [Pubmed]
Segregation of FRAXE in a large family: clinical, psychometric, cytogenetic, and molecular data. Hamel, B.C., Smits, A.P., de Graaff, E., Smeets, D.F., Schoute, F., Eussen, B.H., Knight, S.J., Davies, K.E., Assman-Hulsmans, C.F., Oostra, B.A. Am. J. Hum. Genet. (1994) [Pubmed]
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]
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]
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]
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]
The identification of a third fragile site, FRAXF, in Xq27--q28 distal to both FRAXA and FRAXE. Hirst, M.C., Barnicoat, A., Flynn, G., Wang, Q., Daker, M., Buckle, V.J., Davies, K.E., Bobrow, M. Hum. Mol. Genet. (1993) [Pubmed]
FRAXE mutation in mentally retarded patients using the OxE18 probe. Mulatinho, M.V., Llerena, J.C., Pimentel, M.M. Int. J. Mol. Med. (2000) [Pubmed]
FMR3 is a novel gene associated with FRAXE CpG island and transcriptionally silent in FRAXE full mutations. Gécz, J. J. Med. Genet. (2000) [Pubmed]
A late origin of DNA replication in the trinucleotide repeat region of the human FMR2 gene. Chastain, P.D., Cohen, S.M., Brylawski, B.P., Cordeiro-Stone, M., Kaufman, D.G. Cell Cycle (2006) [Pubmed]
Identification of the FRAXE fragile site in two families ascertained for X linked mental retardation. Flynn, G.A., Hirst, M.C., Knight, S.J., Macpherson, J.N., Barber, J.C., Flannery, A.V., Davies, K.E., Buckle, V.J. J. Med. Genet. (1993) [Pubmed]
Studies of FRAXA and FRAXE in women with premature ovarian failure. Murray, A., Webb, J., Grimley, S., Conway, G., Jacobs, P. J. Med. Genet. (1998) [Pubmed]

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