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)

During the past three years, we have conducted fragile X DNA studies for carrier screening and prenatal diagnosis using a previously described PCR protocol that accurately resolves normal FMR1 alleles and premutations and detects most full mutations [Brown et al., JAMA 270:1569-1575, 1996]. A total of 344 pregnant women with a family history of mental retardation of unknown cause were screened and 6 fragile X carriers were identified: two had full mutations, and four had premutations. The mentally retarded relatives of two other women were found to be fragile X positive although the women themselves were not carriers. In all, 6 carriers and 8 fragile X families were identified by this screening. We have also screened 40 pregnant women who were members of previously identified fragile X families, but whose carrier status was unknown. Ten were found to be carriers and were offered prenatal diagnosis. Prospective prenatal testing of 84 carrier women correctly detected 31 fetal samples (19 females, 12 males) with full mutations and 6 with premutations (2 females, 4 males). No false positives but one false negative occurred early on due to undetected maternal cell contamination. In addition, screening of 806 males with developmental delays of unknown cause gave positive results in 33 (4.1%). Potential problems and pitfalls of direct DNA testing are discussed. Because of the proven success of fragile X screening with direct molecular analysis, screening of all undiagnosed individuals with mental retardation and at risk pregnant women should now be considered. The identification of fragile X carriers and prenatal diagnosis of their pregnancies should significantly reduce the prevalence of this syndrome.
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PMID:Prenatal diagnosis and carrier screening for fragile X by PCR. 882 74

Fragile X syndrome is the most common form of familial mental retardation and is one of the world's most common genetic diseases. The inheritance patterns of the disease have many unusual features. It is an X-linked disorder yet there are asymptomatic carrier males. The disease is expressed only when the gene is inherited from the mother. The risk of a carrier woman having a child with the syndrome depends upon her position in the pedigree (the Sherman paradox) and her own intellectual status. The discovery that the disease is due to dynamic mutation (which is a multistage process) that inactivates FMR1 has provided an explanation for the unusual inheritance patterns. The finding of linkage disequilibrium between the fragile X mutations and closely linked DNA markers (haplotype) has required a reinterpretation of this phenomenon for dynamic mutations. Only a small number of normal alleles at the fragile X locus have long stretches of perfect repeat (2% with more than 24 copies) and these form a reservoir of alleles that can increase in length into the premutation range. Dynamic mutation is, so far, an exclusively human phenomenon, but this is probably because it has yet to be discovered in other species. Unusual inheritance patterns are a hallmark of dynamic mutation diseases.
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PMID:Unusual inheritance patterns due to dynamic mutation in fragile X syndrome. 882 71

Fragile X syndrome, the most common cause of hereditary mental retardation, results from amplification of a CGG trinucleotide repeat in the FMR1 gene. The transmission of the CGG repeat from premutated individuals to their premutated descendants is usually unstable, showing an increase in the size of the repeat. We report here a family which exhibits recurrent and unexpected transmission of the maternal premutation to three daughters. The first daughter exhibited mosaicism with two premutated alleles, one contracted and the other expanded. The second daughter showed a reversion from the maternal premutation to the normal range, and the third carried an expanded premutated allele associated with an expanded paternal allele within the normal range. These variations in the size of the CGG repeat may result from many different mechanisms such as DNA polymerase slippage on the leading or lagging strand during replication, large contractions of repeats on the parental strand during replication, or recombination through unequal crossover between sister chromatids. Our results suggest that the variation of the CGG premutated alleles in this family may be the result of intrinsic instability associated with a trans-acting factor such as a mismatch repair gene product.
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PMID:Recurrent and unexpected segregation of the FMR1 CGG repeat in a family with fragile X syndrome. 883 53

Fragile X syndrome is a frequent cause of mental retardation resulting from the absence of FMRP, the protein encoded by the FMR1 gene. FMRP is an RNA-binding protein of unknown function which is associated with ribosomes. To gain insight into FMRP function, we performed immunolocalization analysis of FMRP truncation and fusion constructs which revealed a nuclear localization signal (NLS) in the amino terminus of FMRP as well as a nuclear export signal (NES) encoded by exon 14. A 17 amino acid peptide containing the FMRP NES, which closely resembles the NES motifs recently described for HIV-1 Rev and PKI, is sufficient to direct nuclear export of a microinjected protein conjugate. Sucrose gradient analysis shows that FMRP ribosome association is RNA-dependent and FMRP is found in ribonucleoprotein (RNP) particles following EDTA treatment. These data are consistent with nascent FMRP entering the nucleus to assemble into mRNP particles prior to export back into the cytoplasm and suggests that fragile X syndrome may result from altered translation of transcripts which normally bind to FMRP.
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PMID:The fragile X mental retardation protein is a ribonucleoprotein containing both nuclear localization and nuclear export signals. 884 25

Only one missense mutation, an Ile304Asn, has been reported in the fragile X gene (FMR1). This mutation is located in the second KH domain of FMR1, and has led to the discovery of the function of the FMR1 gene product as an RNA-binding protein. The patient carrying this mutation has profound mental retardation, macroorchidism, and an "acromegalic" face with prominent supraorbital ridges, enlarged jaw, heavy brow ridges, thick lips, and a broad nose. We have studied the possible involvement of FMR1 in two maternal half-brothers with a phenotype similar to that of the patient with the Ile304Asn mutation. Both brothers had an identical number of CGG repeats in the normal size-range, and shared the same maternal Xq27 haplotype. Southern blot analysis with two overlapping FMR1 cDNA clones, spanning the total FMR1 open reading frame, showed no major deletions, insertions, or gross rearrangements. Single-strand conformation pattern (SSCP) analysis of the KH domains showed no aberrant patterns. The total open reading frame of the FMR1 gene was cloned and sequenced, but no mutation was found. Northern blot analysis showed mRNA in the normal size-range, and immunocytochemistry on individual lymphocytes indicated that FMRP, the protein product of FMR1, was present. In conclusion, it is unlikely that FMR1 plays a role in the phenotype of this patient. Other genes may be responsible for the combination of mental retardation and macroorchidism.
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PMID:Severe mental retardation and macroorchidism without mutation in the FMR1 gene. 884 93

The fragile X (fra-X) syndrome is the most frequent form of inherited mental retardation. Facial dysmorphism, macroorchidism and a folate-sensitive fragile site on Xq27.3 are commonly associated features. The gene causing this disorder, designated as FMR1, is X-linked and shows an unusual inheritance mode. A multistep amplification of the CGG repeats at the 5' end of the FMR1 gene has been recently identified as the cause of the fra-X syndrome. Different numbers of repeats define three gene forms (normal, premutated and mutated), whose ranges show little variation in the populations studied so far. We analyzed 18 Mexican individuals with the fra-X syndrome, 40 of their relatives (first and second degree), and 76 healthy individuals without antecedents of mental retardation. Southern blot and PCR permitted the assessment of the number of CGG repeats and the methylation state of the FMR1 gene for the normal, premutated, and mutated alleles. The results showed no statistical differences when compared with those from other populations. No cytogenetic expression of the Xq27.3 fragile site in 50% of the affected males and in all the affected and carrier females was observed. This finding emphasizes the necessity of a molecular analysis in fra-X cases and their relatives in order to provide a more adequate genetic counseling.
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PMID:Molecular characterization of the fragile-X syndrome in the Mexican population. 898

Fragile X syndrome results from lack of expression of a functional form of Fragile X mental retardation protein (FMRP), a cytoplasmic RNA-binding protein of uncertain function. Here, we report that FMRP contains a nuclear export signal (NES) that is similar to the NES recently identified in the Rev regulatory protein of human immunodeficiency virus type 1 (HIV-1). Mutation of this FMRP NES results in mis-localization of FMRP to the cell nucleus. The FMRP NES is encoded within exon 14 of the FMR1 gene, thus explaining the aberrant nuclear localization of a natural isoform of FMRP that lacks this exon. The NES of FMRP can substitute fully for the Rev NES in mediating Rev-dependent nuclear RNA export and specifically binds a nucleoporin-like cellular cofactor that has been shown to mediate Rev NES function. Together, these findings demonstrate that the normal function of FMRP involves entry into the nucleus followed by export via a pathway that is identical to the one utilized by HIV-1 Rev. In addition, these data raise the possibility that FMRP could play a role in mediating the nuclear export of its currently undefined cellular RNA target(s).
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PMID:A nuclear role for the Fragile X mental retardation protein. 889 84

Using messenger RNA (mRNA) differential display, we isolated several putative differentially expressed complementary DNAs (cDNAs) from the periimplantation (days 11-12) endometrium of unilaterally pregnant pigs. Nucleotide sequence analysis revealed that one cDNA clone was 87% homologous to human spermidine/ spermine N1-acetyltransferase (SSAT) over a stretch of 201 bp and represents the porcine homologue of this cDNA. A second differentially expressed cDNA encoded the porcine equivalent of the human fragile X mental retardation gene (FMR1), whereas a third specified an open reading frame with significant homology to the Escherichia coli N-acetylglucosamine transfer protein. Because SSAT is the rate-limiting enzyme in polyamine metabolism and polyamines are required cytosolic components for cell growth and differentiation, we characterized the expression of the porcine SSAT gene as a potential marker for endometrial growth and/or differentiation during early pregnancy. Further, using the consensus sequence from human and mouse cDNAs, PCR primers were designed and used to generate a 568-bp cDNA fragment from gravid endometrium that encompassed the entire open reading frame for porcine SSAT and which was subsequently used for Northern hybridization analysis. Two distinct SSAT transcripts, a major species of 1.3 kilobase pairs (kb) and a minor species of 3.5 kb were detected in endometrium, each with similar temporal patterns of expression. The levels of SSAT mRNA were higher (P = 0.03) in gravid than in nongravid uterine endometrium of unilaterally pregnant pigs on days 11-12. Similarly, SSAT mRNAs were more abundant (P = 0.0004) in day 12 pregnant than in day 12 cyclic, and in days 30, 60, 90, and 105 pregnant pig endometria. Uterine endometrial luminal epithelial (LE), glandular epithelial (GE), and stromal (ST) cells expressed the SSAT gene, but mRNA abundance varied among cell types (LE > GE > ST). Expression of SSAT gene in ovariectomized gilts treated with estrogen (E2, 100 microg/day), progesterone (P4, 200 mg/day) or E2 + P4 for 11 days was highest (P = 0.03) in the endometria of the P4 group. In contrast, E2 (10 nM), P4 (10 nM) and E2 + P4 had no effect on SSAT mRNA abundance in uterine endometrial explants from day 12 pregnant pigs. However, steady-state SSAT mRNA levels were induced in day 12 pregnant uterine explants by conditioned medium from day 12 filamentous but not spherical conceptuses. These data demonstrate that the temporal induction of the endometrial SSAT gene during periimplantation is modulated by a factor(s) secreted by the periimplantation conceptus and suggest that this enzyme may have an important role in uterine endometrial growth, remodeling and/or differentiation during periimplantation.
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PMID:Molecular cloning of spermidine/spermine N1-acetyltransferase from the periimplantation porcine uterus by messenger ribonucleic acid differential display: temporal and conceptus-modulated gene expression. 894 Mar 70

Fragile X syndrome is the most common cause of inherited mental retardation. Since the identification of the mutation, a Cytosine-Guanine-Guanine repeat in the Fragile X Mental Retardation (FMR1) gene, the genetic counselling and the diagnosis of the disease have been dramatically improved. The nature of the mutation and its size must be integrated in the calculation of the risk of transmission of mental retardation and in the genetic counselling in the family. Out of 245 patients affected with mental retardation referred to our laboratory, we found 37 (15%) fragile X patients, allowing to screen for the mutation in the family and to propose prenatal diagnosis in carrier females.
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PMID:[Molecular biology of fragile X syndrome: recent data and diagnostic applications]. 899 38

Fragile X syndrome, a leading cause of inherited mental retardation, is attributable to the unstable expansion of a CGG-repeat within the FMR1 gene that results in the absence of the encoded protein. The fragile X mental retardation protein (FMRP) is a ribosome-associated RNA-binding protein of uncertain function that contains nuclear localization and export signals. We show here detailed cellular localization studies using both biochemical and immunocytochemical approaches. FMRP was highly expressed in neurons but not glia throughout the rat brain, as detected by light microscopy. Although certain structures, such as hippocampus, revealed a strong signal, the regional variation in staining intensity appeared to be related to neuron size and density. In human cell lines and mouse brain, FMRP co-fractionated primarily with polysomes and rough endoplasmic reticulum. Ultrastructural studies in rat brain revealed high levels of FMRP immunoreactivity in neuronal perikarya, where it is concentrated in regions rich in ribosomes, particularly near or between rough endoplasmic reticulum cisternae. Immunogold studies also provided evidence of nucleocytoplasmic shuttling of FMRP, which was localized in neuronal nucleoplasm and within nuclear pores. Moreover, labeling was observed in large- and small-caliber dendrites, in dendritic branch points, at the origins of spine necks, and in spine heads, all known locations of neuronal polysomes. Dendritic localization, which was confirmed by co-fractionation of FMRP with synaptosomal ribosomes, suggests a possible role of FMRP in the translation of proteins involved in dendritic structure or function and relevant for the mental retardation occurring in fragile X syndrome.
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PMID:Fragile X mental retardation protein: nucleocytoplasmic shuttling and association with somatodendritic ribosomes. 903 Jun 14


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