Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025362 (mental retardation)
 15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Early menopause in the fragile X carriers has been well documented in several reports. All surveys demonstrated that 13-25% of fragile X carriers experienced premature ovarian failure (POF), defined as menopause before the age of 40 years. In 1995 we started screening two groups of subjects as a part of a Fragile X Research Program: 1) women previously diagnosed as fragile X carriers from the register of our center and 2) women with POF and without a family history of fragile X or other forms of mental retardation. In this study we report the preliminary data collected from 75 fragile X families; in 30 of them, POF was present in one or several subjects, all of whom had a fragile X premutation. None of the women with a full mutation experienced POF in our series of patients. We also identified 89 families without a family history of fragile X or mental retardation, and there were 108 subjects who experienced POF, of which 6.5% had a fragile X premutation. This is 70-fold higher than the background prevalence of fragile X premutation in the Italian population and suggests an association with POF. These data confirm the results of other surveys.
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PMID:Premature ovarian failure (POF) and fragile X premutation females: from POF to to fragile X carrier identification, from fragile X carrier diagnosis to POF association data. 1033 12

A map has been assembled that extends from the XY homology region in Xq21.3 to proximal Xq24, approximately 20 Mb, formatted with 200 STSs that include 25 dinucleotide repeat polymorphic markers and more than 80 expressed sequences including 30 genes. New genes HTRP5, CAPN6, STPK, 14-3-3PKR, and CALM1 and previously known genes including BTK, DDP, GLA, PLP, COL4A5, COL4A6, PAK3, and DCX are localized; candidate loci for other disorders for which genes have not yet been identified, including DFN-2, POF, megalocornea, and syndromic and nonsyndromic mental retardation, are also mapped in the region. The telomeric end of the contig overlaps a yeast artificial chromosome (YAC) contig from Xq24-q26 and with other previously published contigs provides complete sequence-tagged site (STS)/YAC-based coverage of the long arm of the X chromosome. The order of published landmark loci in genetic and radiation hybrid maps is in general agreement. Combined with high-density STS landmarks, the multiple YAC clone coverage and integrated genetic, radiation hybrid, and transcript map provide resources to further disease gene searches and sequencing.
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PMID:Integrated STS/YAC physical, genetic, and transcript map of human Xq21.3 to q23/q24 (DXS1203-DXS1059). 1036 51

A total of 106 women affected by premature ovarian failure (POF) were evaluated for fragile X (FRAXA) premutation. The POF patients were classified as having a familial condition (33 women), at least one relative with early menopause (12 women), or a sporadic condition (61 women). The FRAXA premutation was only detected in patients with familial (four out of 33) or sporadic POF (two out of 61). In general, the results obtained indicated that the prevalence [six out of 106, 6%, 95% confidence interval (CI) 3-11%] of FRAXA premutation is significantly higher in women affected by POF than expected (P = 1.24x10(-3)), suggesting a phenotype consequence of the premutation alleles. This relationship is more convincingly derived from the observation in two analysed pedigrees of a co-segregation between FRAXA and POF. These findings suggest a possible involvement of premutated alleles in ovarian failure, and indicate the utility of POF families screening for FRAXA premutation in order to prevent the transmission of mental retardation syndrome.
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PMID:Association between idiopathic premature ovarian failure and fragile X premutation. 1092 Jan 20

Taxonomic features of fragile X syndrome (FXS) associated with the fragile X mutation have evolved over several decades. Males are more severely impacted cognitively than females, but both show declines in IQ scores as they age. Although many males with FXS exhibit autistic-like features, autism does not occur more frequently in males with FXS than among males with mental retardation (MR). FXS is caused by inactivation of the FMR1 gene located on Xq27.3. FMRP, the protein produced by FMR1, has been detected in most organs and in brain. In cells, it is located primarily in cytoplasm and contains motifs found in RNA-binding proteins. The FMRP N-terminal contains a functional nuclear localization signal which permits the protein to shuttle between cytoplasm and nucleus. FMR1 knockout mice show subtle behavioral and visual-spatial difficulties. Analysis of their brain tissue suggests absence of FMRP impairs synaptic maturation. Individuals with the fragile premutation produce FMRP, and the phenotype associated with the premutation has been controversial. However, there seems to be a higher incidence of premature ovarian failure in women with the premutation than is found in the general female population. This may be related to unusual increases in mRNA levels in premutation carriers.
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PMID:FMR1 gene and fragile X syndrome. 1118 Feb 23

FMR1 is an X-linked gene that codes for an RNA binding protein. Expansion of a triplet repeat within exon 1 of the gene causes the fragile X syndrome, which is characterized by mental retardation and various physical anomalies. The triplet repeat in FMR1 can expand to varying degrees. Only the very large expansions in which there is concomitant methylation of the gene cause the fragile X syndrome. Expansions of between 50 and 200 repeats are premutations. Although premutations were originally perceived to be without phenotypic effect, there is now substantial evidence that female carriers of premutations are at increased risk of having early menopause. The FMR1 premutation is also associated with a significant number of cases ascertained because of idiopathic premature ovarian failure, particularly when ovarian failure is a familial trait. The molecular mechanism to explain the association between ovarian failure and premutations is unknown.
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PMID:Premature ovarian failure and the FMR1 gene. 1129 21

Nearly 15 years ago, female carriers of the fragile X mental retardation syndrome were noted to have an increased incidence of twin pregnancies. Since then, much evidence has accumulated supporting the notion of ovarian dysfunction in fragile X carriers, in the forms of increased dizygotic twinning and premature ovarian failure. However, despite a decade and a half of research regarding this association, the underlying mechanism remains a mystery. This article reviews the population-based studies that have examined this association and discusses possible reasons for the variations in results. In addition, results from more recent studies on endocrine function in fragile X carriers are discussed. These data, when considered in conjunction with our emerging understanding of the molecular biology of the fragile X gene (FMR1) and its protein product (FMRP), are beginning to elucidate possible mechanisms for the association between fragile X syndrome and ovarian dysfunction.
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PMID:The female and the fragile X reviewed. 1148 Sep 13

Fragile X syndrome is the most common form of inherited mental retardation in men. The molecular mechanism underlying the disease is an amplification of a polymorphic trinucleotide repeat (CGG)n located at 5' end of FMR1 which promotes transcriptional silencing of the gene. Four different classes of alleles could be distinguished in the population based on the size of the repeat, however only large amplifications over 200 CGG are associated with the disease. In the past decade several authors have associated premutated alleles, which harbor expansions from 61 to 200 repeats, with the occurrence of premature ovarian failure (POF). In this work we describe a large Brazilian family in which a POF/premutated woman has transmitted to five out of seven daughters a FMR1 premutated allele. From these five women with premutations, three have experienced premature ovarian failure. Our data clearly indicate a co-segregation pattern of inheritance between POF and fragile X premutation.
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PMID:Premature ovarian failure and FMR1 premutation co-segregation in a large Brazilian family. 1211 65

Premature ovarian failure (POF) and underlying hormonal changes are recognized as a distinct phenotype in female fragile-X premutation carriers. Neurocognitive deficits, in particular mental retardation, are associated with the full mutation in males and females. In female full mutation carriers this neurocognitive phenotype is expressed more mildly than in males. Research on whether the fragile-X premutation is associated with a particular neurocognitive phenotype or not has been equivocal. By means of the Sonneville Visual Attentions Tasks (SVAT) computer-based battery of neurocognitive tasks, we assessed reaction time on different tasks in three groups of subjects: female premutation carriers, female full mutation carriers, and female control subjects. The results show that a fraction of the female premutation carriers perform poorly on several selective attention tasks, but not on other tasks. Their neurocognitive profile is different from that of control subjects and of the majority of female premutation carriers. It may also be different from the phenotype of female full mutation carriers, though in that respect this study remains inconclusive. These findings support earlier findings that the fragile-X premutation may affect neurocognitive functioning, in particular aspects of attention.
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PMID:A distinct neurocognitive phenotype in female fragile-X premutation carriers assessed with visual attention tasks. 1247 50

Blepharophimosis syndrome (BPES), an autosomal dominant syndrome in which an eyelid malformation is associated (type I) or not (type II) with premature ovarian failure (POF), has recently been ascribed to mutations in FOXL2, a putative forkhead transcription factor gene. We previously reported 22 FOXL2 mutations and suggested a preliminary genotype-phenotype correlation. Here, we describe 21 new FOXL2 mutations (16 novel ones) through sequencing of open reading frame, 5' untranslated region, putative core promoter, and fluorescence in situ hybridization analysis. Our study shows the existence of two mutational hotspots: 30% of FOXL2 mutations lead to polyalanine (poly-Ala) expansions, and 13% are a novel out-of-frame duplication. In addition, this is the first study to demonstrate intra- and interfamilial phenotypic variability (both BPES types caused by the same mutation). Furthermore, the present study allows a revision of the current genotype-phenotype correlation, since we found exceptions to it. We assume that for predicted proteins with a truncation before the poly-Ala tract, the risk for development of POF is high. For mutations leading to a truncated or extended protein containing an intact forkhead and poly-Ala tract, no predictions are possible, since some of these mutations lead to both types of BPES, even within the same family. Poly-Ala expansions may lead to BPES type II. For missense mutations, no correlations can be made yet. Microdeletions are associated with mental retardation. We conclude that molecular testing may be carefully used as a predictor for POF risk in a limited number of mutations.
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PMID:FOXL2 and BPES: mutational hotspots, phenotypic variability, and revision of the genotype-phenotype correlation. 1252 55

Fragile X syndrome, the most common form of inherited mental retardation, is caused by hyperexpansion and hypermethylation of a CGG repeat tract in the 5' untranslated region of the FMR1 gene. This methylation causes the gene to be transcriptionally silenced. In addition to the common allele form with less than 41 repeats, there are two other allelic forms of the FMR1 gene that are unmethylated: premutation (61-200 CGG repeats) and intermediate (41-60 CGG repeats). Recently, premutation-specific phenotypes not related to fragile X syndrome have been reported: a 20-fold increased risk for premature ovarian failure (POF) among female carriers and an increased risk for a tremor ataxia syndrome (TAS) primarily among older male carriers. At the molecular level, increased levels of FMR1 transcript have been observed among premutation carriers. Increased levels of transcript may be causally related to the POF or TAS phenotypes or may be a surrogate of some other allelic property. In this report, we have examined the distributional properties of transcript levels by repeat size and gender among 238 individuals. We have confirmed a significant linear relationship between transcript level and repeat size in males and females. The evidence for the linear effect is primarily within the premutation size alleles.
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PMID:A study of the distributional characteristics of FMR1 transcript levels in 238 individuals. 1475 38


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