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Query: UMLS:C0917816 (mental retardation)
 15,867 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The fragile X syndrome is the most common cause of familial intellectual disability. The identification of the 'fragile-X mental retardation' (FMR1) gene disclosed a novel genetic mechanism: an intergenerational instable cytosine-guanine-guanine (CGG) repeat leading to the absence of FMR1 protein above a threshold of 200 repeats and, subsequently, leading to familial mental retardation.
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PMID:[From gene to disease; fragile X-syndrome: hereditary mental retardation due to a developmental gene]. 1126 9

Fragile X syndrome generally arises as a consequence of a large expansion of a CGG trinucleotide repeat element that is located in the GC-rich promoter region of the fragile X mental retardation gene (FMR1). In the conventional model for fragile X, clinical involvement arises as a consequence of silencing of the FMR1 gene, with the attendant loss of FMR1 protein (FMRP). However, it has recently been demonstrated that most males with large premutation alleles (100-200 repeats), or with unmethylated full mutation alleles, have FMR1 mRNA levels that are higher than normal, despite reduced levels of FMRP. In the current work, we extend and confirm these observations using quantitative (fluorescent) reverse transcription polymerase chain reaction on larger sample populations, establishing that even for smaller premutation alleles (55-100 repeats) the mRNA levels are significantly elevated (mean 2.1-fold elevation; P = 3.9 x 10(-3)), relative to normal controls. Thus, an abnormal molecular phenotype is established close to the upper end of the normal range. We also demonstrate that the levels of FMR1 mRNA are elevated in females with premutation alleles; however, the mRNA levels are more varied than in the males, and are attenuated in a manner that is consistent with the fraction of normal alleles that are active in any given individual. Finally, we demonstrate that in lymphoblastoid cells derived from a patient with a severe form of fragile X caused by a point mutation in the second KH domain of the gene, but with a normal CGG element (25 repeats), the FMR1 mRNA level is normal. Thus, although models in which FMRP level (or level of function) modulates transcriptional activity remain viable, other explanations for the elevated message levels, including direct (cis) effects of the CGG element on transcription, must also be considered.
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PMID:Transcription of the FMR1 gene in individuals with fragile X syndrome. 1144 88

Fragile X syndrome is a common form of mental retardation caused by the absence of the FMR1 protein, FMRP. Fmr1 knockout mice exhibit a phenotype with some similarities to humans, such as macro-orchidism and behavioral abnormalities. Two homologs of FMRP have been identified, FXR1P and FXR2P. These proteins show high sequence similarity, including all functional domains identified in FMRP, such as RNA binding domains. They have an overlap in tissue distribution to that of FMRP. Interactions between the three FXR proteins have also been described. FXR2P shows high expression in brain and testis, like FMRP. To study the function of FXR2P, we generated an Fxr2 knockout mouse model. No pathological differences between knockout and wild-type mice were found in brain or testis. Given the behavioral phenotype in fragile X patients and the phenotype previously reported for the Fmr1 knockout mouse, we performed a thorough evaluation of the Fxr2 knockout phenotype using a behavioral test battery. Fxr2 knockout mice were hyperactive (i.e. traveled a greater distance, spent more time moving and moved faster) in the open-field test, impaired on the rotarod test, had reduced levels of prepulse inhibition, displayed less contextual conditioned fear, impaired at locating the hidden platform in the Morris water task and were less sensitive to a heat stimulus. Interestingly, there are some behavioral phenotypes in Fxr2 knockout mice which are similar to those observed in Fmr1 knockout mice, but there are also some different behavioral abnormalities that are only observed in the Fxr2 mutant mice. The findings implicate a role for Fxr2 in central nervous system function.
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PMID:Knockout mouse model for Fxr2: a model for mental retardation. 1187 43

Fragile X syndrome is a common X-linked hereditary disease, characterized by mental retardation, macroorchidism and mild facial abnormalities and is almost always caused by the absence or deficit of the FMR1 protein. In the majority of cases, the disease is associated with an expansion of a CGG repeat, located in the 5' UTR of the FMR1 gene. Diagnostic methods include PCR amplification and Southern blotting, which are performed on DNA isolated from peripheral leukocytes. Recently, varying immunocytochemical tests have been described to identify fragile X patients, based on the detection of FMR1 protein in cells by a monoclonal antibody. This review provides an update on the different DNA methods and gives specific attention to both the newly developed PCR method and antibody methods for prenatal and postnatal diagnosis of the fragile X syndrome.
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PMID:Diagnostic tests for fragile X syndrome. 1190 18

Arithmetic processing deficits in persons with fragile X Syndrome (fraX), the most common heritable cause of mental retardation, are well known. In this study, we characterize the neural underpinnings of these performance deficits using functional MRI. Given that a single gene defect (FMR1) is known to be responsible for this disorder, we also assess whether brain activation in arithmetic processing areas is related to amount of FMR1 protein expression (FMRP). Subjects included 16 females with fraX, and 16 female age-matched controls. Subjects viewed arithmetic equations with two (1 + 3 = 4) or three (2 + 3 - 1 = 5) operands, and were asked to judge whether the results were correct or not. Subjects with fraX showed significant impairment in behavioral performance on the 3-operand but not the 2-operand arithmetic equations. Significant brain activation was observed bilaterally in the prefrontal and parietal cortices for unaffected subjects, and bilateral prefrontal and left angular gyrus for subjects with fraX, for both trial types. Subjects with fraX exhibited less overall activation than did unaffected subjects in both types of trials; and, unlike the unaffected group, did not show increased extent of activation in association with greater task difficulty. During the 3-operand trials, activation in bilateral prefrontal and motor/premotor, and left supramarginal and angular gyri were positively correlated with FMRP, suggesting that decreased FMR1 protein expression underlies deficits in math performance in persons with fraX. More broadly, this investigation demonstrates a unique bridging of cognitive and molecular neuroscience and represents a useful approach for the study of brain development and function.
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PMID:Functional brain activation during arithmetic processing in females with fragile X Syndrome is related to FMR1 protein expression. 1211 63

In fragile X syndrome, hypermethylation of the expanded CGG repeat and of the upstream promoter leads to transcriptional silencing of the FMR1 gene. Absence of the FMR1 protein results in mental retardation. We previously proved that treatment with 5-azadeoxycytidine (5-azadC) of fragile X cell lines results in reactivation of the FMR1 gene. We now show that this treatment causes passive demethylation of the FMR1 gene promoter. We employed the bisulfite-sequencing technique to detect the methylation status of individual CpG sites in the entire promoter region, upstream of the CGG repeat. Lymphoblastoid cell lines of fragile X males with full mutations of different sizes were tested before and after treatment with 5-azadC at various time points. We observed that individual cells are either completely unmethylated or not, with few relevant exceptions. We also investigated the extent of methylation in the full mutation (CGG repeat) itself by Southern blot analysis after digestion with methylation-sensitive enzymes Fnu4HI and McrBC and found that the CGG repeat remains at least partially methylated in many cells with a demethylated promoter. This may explain the quantitative discrepancy between the large extent of promoter demethylation and the limited levels of FMR1 transcriptional reactivation estimated by quantitative real-time fluorescent RT-PCR analysis.
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PMID:Quantitative analysis of DNA demethylation and transcriptional reactivation of the FMR1 gene in fragile X cells treated with 5-azadeoxycytidine. 1213 10

Mutations that abolish expression of an X-linked gene, FMR1, result in the pathogenesis of fragile X syndrome, the most common form of inherited mental retardation. To understand the normal function of the FMR1 protein, we have produced fly strains bearing deletions in a Drosophila homolog of FMR1 (dfmr1). Since fragile X patients show a number of abnormal behaviors including sleep problems, we investigated whether a loss-of-function mutation of dfmr1 affect circadian behavior. Here we show that under constant darkness (DD), a lack of dfmr1 expression causes arrhythmic locomotor activity, but in light:dark cycles, their behavioral rhythms appear normal. In addition, the clock-controlled eclosion rhythm is normal in DFMR1-deficient flies. These results suggest that DFMR1 plays a critical role in the circadian output pathway regulating locomotor activity in Drosophila.
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PMID:A role for the Drosophila fragile X-related gene in circadian output. 1217 63

Fragile X syndrome is a common form of inherited mental retardation caused by the loss of FMR1 expression. The FMR1 gene encodes an RNA-binding protein that associates with translating ribosomes and acts as a negative translational regulator. In Drosophila, the fly homolog of the FMR1 protein (dFMR1) binds to and represses the translation of an mRNA encoding of the microtuble-associated protein Futsch. We have isolated a dFMR1-associated complex that includes two ribosomal proteins, L5 and L11, along with 5S RNA. The dFMR1 complex also contains Argonaute2 (AGO2) and a Drosophila homolog of p68 RNA helicase (Dmp68). AGO2 is an essential component for the RNA-induced silencing complex (RISC), a sequence-specific nuclease complex that mediates RNA interference (RNAi) in Drosophila. We show that Dmp68 is also required for efficient RNAi. We further show that dFMR1 is associated with Dicer, another essential component of the RNAi pathway, and microRNAs (miRNAs) in vivo, suggesting that dFMR1 is part of the RNAi-related apparatus. Our findings suggest a model in which the RNAi and dFMR1-mediated translational control pathways intersect in Drosophila. Our findings also raise the possibility that defects in an RNAi-related machinery may cause human disease.
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PMID:A Drosophila fragile X protein interacts with components of RNAi and ribosomal proteins. 1236 61

The fragile X mental retardation syndrome is caused by large methylated expansions of a CGG repeat in the FMR1 gene leading to the loss of expression of FMRP, an RNA-binding protein. FMRP is proposed to act as a regulator of mRNA transport or translation that plays a role in synaptic maturation and function. To study the physiological function of the FMR1 protein, mouse and Drosophila models have been developed. The loss-of-function mouse model shows slightly enlarged testes, a subtle behavioral phenotype, and discrete anomalies of dendrite spines similar to those observed in brains of patients. Studies in Drosophila indicate that FXMR plays an important role in synaptogenesis and axonal arborization, which may underlie the observed deficits in flight ability and circadian behavior of FXR mutant flies. The relevance of these studies to our understanding of fragile X syndrome is discussed.
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PMID:Understanding fragile X syndrome: insights from animal models. 1452 71

It is currently thought that fragile X syndrome (FraX; the most common inherited form of learning disability) results from having more than 200 cytosine-guanine-guanine (CGG) trinucleotide repeats, with consequent methylation of the fragile X mental retardation (FMR1) gene and loss of FMR1 protein (FMRP). It was also considered that premutation carriers (with 55-200 CGG repeats) are unaffected, although a tremor/ataxia syndrome has recently been described in older adult male carriers. We reported that premutation expansion of CGG trinucleotide repeats affects brain anatomy, which, together with other studies, indicates that the molecular model for FraX needs modification. However, there are few studies on the cognitive ability of adult male premutation carriers. Thus, we selected 20 male premutation carriers on the basis of their genetic phenotype, and compared them to 20 male controls matched on age, IQ and handedness. We investigated intellectual functioning, executive function, memory, attention, visual and spatial perception, and language and pragmatics. The premutation carriers had significant impairments on tests of executive function (Verbal Fluency, Trail Making Test and Tower of London) and memory (Names sub-test of the Doors and People, Verbal Paired Associates Immediate Recall and Visual Paired Associates Delayed Recall sub-tests of the WMS-R, and Category Fluency Test for natural kinds). We therefore suggest that CGG trinucleotide repeats in the premutation range affect specific neuronal circuits that are concordant with specific neuropsychological deficits; and that these deficits reflect an emerging neuropsychological phenotype of premutation FraX.
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PMID:A neuropsychological investigation of male premutation carriers of fragile X syndrome. 1538 Oct 24


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