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)

Fragile-X syndrome, the most common inherited form of mental retardation, has a very unusual mode of inheritance. The disease is caused by a multistep expansion, in successive generations, of a polymorphic CGG repeat localized in a 5' exon of FMR-1, a gene of unknown function. Two main mutation types have been categorized. Premutations are moderate expansions of the repeat and do not cause mental retardation. Full mutations are found in affected individuals and involve larger expansions of the repeat, with abnormal methylation of the neighboring CpG island. The full mutations demonstrate striking somatic instability and extinguish expression of FMR-1. Premutations are changed to full mutation only when transmitted by a female with a frequency that increases up to 100% as a function of the initial size of the premutation. Direct detection of the mutations provides an accurate test for pre- and postnatal diagnosis of the disease, and for carrier detection. A similar unstable expansion of a trinucleotide repeat occurs in myotonic dystrophy.
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PMID:Molecular genetics of the fragile-X syndrome: a novel type of unstable mutation. 150 17

Fragile X syndrome is one of the most common human genetic diseases and the most common cause of hereditary mental retardation. The gene that causes fragile X syndrome, FMR1, was recently identified and sequenced and found to encode a putative protein of unknown function. Here we report that FMR1 contains two types of sequence motifs recently found in RNA-binding proteins: an RGG box and two heterogeneous nuclear RNP K homology domains. We also demonstrate that FMR1 binds RNA in vitro. Using antibodies to FMR1, we detect its expression in divergent organisms and in cells of unaffected humans, but fragile X-affected patients express little or no FMR1. These findings demonstrate that FMR1 expression is directly correlated with the fragile X syndrome and suggest that anti-FMR1 antibodies will be important for diagnosis of fragile X syndrome. Furthermore, the RNA binding activity of FMR1 opens the way to understanding the function of FMR1.
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PMID:The protein product of the fragile X gene, FMR1, has characteristics of an RNA-binding protein. 768 65

A new gene (239FB) with predominant and differential expression in fetal brain has recently been isolated from a chromosome 11p13-p14 boundary area near FSHB. The corresponding mRNA has an open reading frame of 294 amino acids, a 3' untranslated region of 1247 nucleotides, and a highly GC-rich 5' untranslated region. The coding and 3' UT sequence is specified by 6 exons within nearly 87 kb of isolated genomic locus. The 5' end region of the transcript maps adjacent to the only genomically defined CpG island in a chromosomal subregion that may be associated with part of the mental retardation of some WAGR (Wilms tumor, aniridia, genitourinary anomalies, and mental retardation) syndrome patients. In addition to nucleotide and amino acid similarity to an EST from a normalized infant brain cDNA library, the predicted protein has extensive similarity to two Caenorhabditis elegans polypeptides of, as yet, unknown function. The 239FB locus is, therefore, likely part of a family of genes with two members expressed in human brain. The extensive conservation of the predicted protein suggests a fundamental function of the gene product and will enable evaluation of the role of the 239FB gene in neurogenesis in model organisms.
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PMID:cDNA sequence, genomic organization, and evolutionary conservation of a novel gene from the WAGR region. 866 3

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

FMR1 (Fra X Mental Retardation 1), a gene of unknown function, is responsible for an important hereditary mental retardation, the fragile X syndrome. In this study, a 22-bp enhancer (methylation sensitive element, MSE) in the FMR1 promoter was defined by DNase I footprinting assay, and the binding of this element by nuclear factor was prevented by DNA CpG methylation. A cAMP-responsive element (CRE)-like sequence and a myc-binding sequence in MSE were identified. In the transfection assay, MSE demonstrated a strong, methylation-sensitive enhancer activity. MSE could be bound by recombinant CRE-binding protein (CREB), and its activity was stimulated by CREB in a co-transfection assay. In PC12 cells, forskolin elevated MSE activity several fold, and this induction was abolished in CRE mutants. The involvement of cAMP in the expression of FMR1 should be a clue to both the function of FMR1 and the pathogenesis of fragile X syndrome.
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PMID:FMR1 enhancer is regulated by cAMP through a cAMP-responsive element. 915 Apr 32

A novel family of genes expressed in human brain has recently been identified. Gene 239FB, transcribed extensively in fetal brain, was isolated from the chromosome 11p13 region associated with mental retardation component of the WAGR (Wilms tumor, aniridia, genitourinary anomalies, mental retardation) syndrome. This report presents a cDNA sequence and expression profile of a related gene, 239AB, isolated from adult brain library, that was mapped to chromosome 22. While similar in structure, the two genes differ in their expression pattern and may have different roles in central nervous system development and function. In contrast to the 239FB, which is expressed predominantly in fetal brain, the 239AB gene is transcribed in adult tissues. Both human genes encode novel proteins of unknown function that are highly conserved from Caenorhabditis elegans to birds and mammals. Phylogenetic analysis suggested that the two lineages of the ancient gene family represented by 239FB and 239AB have been in existence prior to the emergence of modern animals.
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PMID:The 239AB gene on chromosome 22: a novel member of an ancient gene family. 926 72

Down syndrome, caused by trisomy of human chromosome 21 (HSA21), is the most common autosomal form of mental retardation. To understand the aetiology of the syndrome we need to identify the genes involved. We have utilised the information generated by the various EST sequencing projects to enrich the transcription map of chromosome 21. Here we report the mapping of SH3P17 to 21q22.1 and the localisation of two genes previously mapped to HSA21 by Nagase and colleagues, KIAA0136 and KIAA0179 to 21q22.2 and 21q22.3, respectively. SH3P17 has unknown function but contains four SH3 domains. KIAA0136 shows no homology to a yeast open reading frame. Further investigation of these three genes will add to our functional understanding of HSA21.
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PMID:Mapping of a novel SH3 domain protein and two proteins of unknown function to human chromosome 21. 927 76

FMR2 is the gene associated with FRAXE mental retardation. It is expressed as an 8.7-kb transcript in placenta and adult brain. A fetal-specific FMR2 transcript of approximately 12 kb was detected in fetal brain and at a lower level in fetal lung and kidney. FMR2 is a large gene composed of 22 exons spanning at least 500 kb on Xq28. Alternative splicing involving exons 2, 3, 5, 7, and 21 was not tissue specific as tested on mRNA from human fetal and infant brain. FMR2 is translated into a 1311-amino-acid nuclear protein with putative transcription transactivation potential. Subcellular localization studies with green fluorescent protein as a reporter show that both nuclear addresses found in the FMR2 sequence are functional and direct the FMR2 protein into the nucleus. FMR2 together with AF4 and LAF4 forms a new family of nuclear proteins with DNA-binding capacity and transcription transactivation potential. BLAST searches of the dbEST database revealed the presence of at least two other groups of nonoverlapping ESTs showing high similarity to the FMR2-related family of proteins. One of them, represented by the EST W26686, maps to chromosome 5q31. Amino acid similarity among the proteins encoded by members of the gene family is high in the NH2 terminus, low in the middle, and high again in the COOH end. Available information from members of the family shows that genomic organization is conserved. This FMR2-related gene family encodes nuclear proteins with involvement in mental retardation (FMR2), cancer (AF4), and lymphocyte differentiation (LAF4) or with unknown function (EST W26686 and/or AA025630).
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PMID:Gene structure and subcellular localization of FMR2, a member of a new family of putative transcription activators. 929 37

The fragile X syndrome is due to the new class of dynamic mutations. It is associated with an expansion of a trinucleotide repeat (CGG) in exon 1 of the fragile X mental retardation gene 1 gene (FMR1). Here we present a fragile X family with an unique female patient who was rendered hemizygous for the FRAXA locus due to a large deletion of one X chromosome. In addition, the other X had a microdeletion in FMR1. PCR and sequence analysis revealed that the microdeletion included all CGG repeats plus 97 bp of flanking sequences, leaving transcription start site and translation start site intact. Despite this total lack of CGG repeats in the FMR1 gene, Western blot analysis showed expression of FMRP, and the patient's phenotype was essentially normal. X-inactivation studies of the androgen-receptor (AR) locus and haplotype determination of microsatellite markers gave evidence that the deletion probably originated from regression of a fully mutated FMR1 gene. Although the minimal number of CGG repeats hitherto reported in FRAXA is six, and at least four other genes associated with CGG repeats are known, suggesting an as yet unknown function of these repeats, our study clearly demonstrates that the absence of CGG repeats does not abolish expression of the FMR1 gene in lymphoblastoid cells.
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PMID:Deletion of all CGG repeats plus flanking sequences in FMR1 does not abolish gene expression. 938 10

Fragile X syndrome is the most frequent form of inherited mental retardation and it is caused by deficiency of FMRP, the protein encoded by the FMR1 gene. FMRP is a RNA binding protein of unknown function which is associated with ribosomes. FMRP is found in the cytoplasm, but it is endowed with a nuclear export signal (NES), encoded by exon 14, and a nuclear localization signal (NLS). Characterization of the FMRP NES and NLS domains is presented here. We show by site-directed mutagenesis that three leucine residues in exon 14 are functionally important for the cytoplasmic localization of FMRP. Changing these leucines to serine resulted in a nuclear localization, while another nonconservative change (leucine to tyrosine) did not show such an effect. We also show that the NLS activity is localized between residues 115 and 150, a region that lacks stretches of basic residues. Such stretches are typical of nuclear localization signals that act through the important alpha pathway. The region between residues 151 and 196 can reinforce the NLS activity. A truncated construct containing the N-terminal region of FMRP (residues 1-114) is strikingly concentrated in the nucleus. This suggests that it may contain a domain of strong affinity with a nuclear component.
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PMID:Analysis of domains affecting intracellular localization of the FMRP protein. 944 Jan 21


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