FMR2 Expression in Families with Fraxe Mental Retardation

Gécz, Jozef; Oostra, Ben A.; Hockey, Athel; Carbonell, Pablo; Turner, Gillian; Haan, Eric; Sutherland, Grant R.; Mulley, John C.

doi:10.1093/hmg/6.3.435

Cited by 58 publications

(57 citation statements)

References 26 publications

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“…Such incomplete penetrance has been also observed in other X-Chromosome MR syndromes including Fragile X, where approximately 20% of males carrying the mutation are unaffected 22,23 and in FRAXE, where 45% (5/11) of individuals in a series of cases were unaffected. 24 Alternatively, given our limited physical characterization of the affected individuals, we may not have identified the full spectrum of clinical presentation. MR may not be the defining feature but rather an extreme manifestation of the affected spectrum of this syndrome.…”

Section: Discussionmentioning

confidence: 99%

Association of an X-chromosome dodecamer insertional variant allele with mental retardation

Philibert¹,

Bh²,

Winfield³

et al. 1998

Mol Psychiatry

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Mental retardation is a prominent feature of many neurodevelopmental syndromes. In an attempt to identify genetic components of these illnesses, we isolated and sequenced a large number of human genomic cosmid inserts containing large trinucleotide repeats. One of these cosmids, Cos-4, maps to the X-chromosome and contains the sequence of a 7.3-kb mRNA. Initial polymorphism analysis across a region of repetitive DNA in this gene revealed a rare 12-bp exonic variation ( 1% in non-ill males) having an increased prevalence in non-Fragile X males with mental retardation (4%, P Ͻ0.04, n = 81). This variant was not present in the highly conserved mouse homologue that has 100% amino acid identity to the human sequence near the polymorphism. Subsequent screening of two additional independent cohorts of non-Fragile X mentally retarded patients and ethnically matched controls demonstrated an even higher prevalence of the 12-bp variant in males with mental retardation (8%, P Ͻ0.0003, n = 125, and 14%, P Ͻ0.10, n = 36) vs the controls. Multivariate analysis was conducted in an effort to identify other phenotypic components in affected individuals, and the findings suggested an increased incidence of histories of hypothyroidism (P Ͻ0.001) and treatment with antidepressants (P Ͻ0.001). We conclude that the presence of this 12-bp variant confers significant susceptibility for mental retardation.

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Section: Discussionmentioning

confidence: 99%

Association of an X-chromosome dodecamer insertional variant allele with mental retardation

Philibert¹,

Bh²,

Winfield³

et al. 1998

Mol Psychiatry

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“…3 Two major isoforms of FMR2 were described 1,2,8 and characterised. 4 We have identified 3 and characterised (present study) an additional large FMR2 isoform of 13.7 kb. The existence of this FMR2 isoform with predominant expression in foetal brain and adult pituitary gland is puzzling as no additional protein sequence is encoded.…”

Section: Discussionmentioning

confidence: 75%

“…4 Probes were hybridised to the filter overnight following the conditions recommended by the manufacturer and washed several times in 0.5 X SSC, 0.5% SDS at 65°C. Shorter (24 h) and longer (4 days) exposures were taken.…”

Section: Northern Blot Hybridisationmentioning

confidence: 99%

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Characterisation and expression of a large, 13.7 kb FMR2 isoform.

Gécz

Mulley

1999

Eur J Hum Genet

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FMR2 is the gene associated with FRAXE fragile site non-specific mental retardation (FRAXE MRX). Previously a male patient was identified with developmental delay and speech problems who had a deletion within intron 3 of FMR2. No known FMR2 exonic sequences were missing in this patient. Detailed northern blot analysis revealed existence of a new large isoform of FRM2 in foetal brain. This isoform was characterised and found to be due entirely to an addition of an extra 4.9 kb of the 3' UTR to the previously characterised 8.755 kb FMR2 transcript. This excluded involvement of the large FMR2 isoform in the MRX phenotype of three individuals now known to have the same deletion of intron 3 FMR2 sequences. Expression studies on the new 13.7 kb FMR2 isoform show that it is expressed predominantly in foetal brain and adult pituitary gland, whilst the expression of the shorter previously characterised 8.755 kb isoform is broader, including testis, thymus and placenta. Possible consequences of the alternative processing and expression of FMR2 for the molecular pathology of FRAXE MRX are discussed.

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“…[4][5][6][7] Recently, a gene associated to FRAXE and designed as FMR2 has been cloned and shown to be expressed in brain and placenta. 8,9 Loss of FMR2 expression seems to correlate with (GCC) n expansion at FRAXE, suggesting the involvement of this gene in FRAXE-associated mild MR. [8][9][10] However, a few phenotypically normal males have been reported with complete methylation at the FRAXE locus and no FMR2 expression. [6][7][8] …”

Section: Introductionmentioning

confidence: 99%

FRAXE mutation in a mentally retarded subject and in his phenotypically normal twin brother

et al. 2000

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The FRAXE fragile site, 600 kb distal to the more common FRAXA, has been reported to be expressed in subjects with mild non-syndromal mental retardation (MR). Amplification of more than 200 GCC repeats, associated with methylation of the adjacent CpG island at Xq28, leads to the expression of the fragile site. In 1996 a large gene, FMR2, transcribed distally from the CpG island and downregulated by repeat expansion and methylation, was identified. Among 232 mentally retarded patients, tested FRAXA negative, we identified an Italian family segregating a hypermethylated expansion at the FRAXE locus in two dizygotic twin brothers, their sister and their mother. The index case was referred at 23 years of age with severe MR, epilepsy, a dysmorphic face with a high arched palate, marfanoid habitus and hyperreflexia of the lower limbs. His brother was referred to as normal and psychometric tests confirmed he is not mentally retarded. All members of the family underwent FRAXE molecular analysis, after cytogenetic expression of the fraX site and negative FRAXA test. Interestingly, an expansion and a hypermethylation at the FRAXE locus were found in all of them. Fibroblasts from the clinically normal brother were assayed for FMR2 expression and the transcription of the gene was found to be silenced. The presence of a phenotypically normal male with absent FMR2 expression in fibroblasts suggests that the relationship between the FRAXE mutation, FMR2 expression and MR needs to be further investigated. European Journal of Human Genetics (2000) 8, 157-162.

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FMR2 Expression in Families with Fraxe Mental Retardation

Cited by 58 publications

References 26 publications

Association of an X-chromosome dodecamer insertional variant allele with mental retardation

Association of an X-chromosome dodecamer insertional variant allele with mental retardation

Characterisation and expression of a large, 13.7 kb FMR2 isoform.

FRAXE mutation in a mentally retarded subject and in his phenotypically normal twin brother

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