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

The FMR2 gene is dysregulated by the fragile X E triplet repeat expansion in patients with FRAXE mental retardation syndrome. A CCG triplet, located in the 5' untranslated region of the FRAXE gene undergoes expansion and methylation in these patients, eliminating detectable gene transcription. FRAXE syndrome is distinct from fragile X syndrome, a more common genetic form of mental retardation caused by expansion and methylation of a similar repeat in the FMR1 gene located 600 kb proximal to FRAXE. FRAXE syndrome is rare, and patients' phenotypes are highly variable, leading to difficulties with predicting specific FMR2 functions based on the human disease. Recently, Lilliputian(Lilli), a Drosophila FMR2 orthologue, was identified; this gene has been linked with several signal transduction pathways, including the transforming growth factor-beta (TGF-beta) pathway, the Raf/MEK/MAP kinase (MAPK) pathway, and the P13K/PKB pathway. Mutation of Lilli shows defects in germinal band extension, cytoskeletal structure, cell growth, and organ development. The Lilli gene suggests possible functions for FMR2 (and related genes) in humans and mice, but cannot predict specific functions. Modeling FMR2 mutation in the mouse will be useful to understand specific functions of this gene in vertebrates. This review presents what has been learned thus far from the FMR2 knockout mouse model and suggests future studies on this model in order to compare it with the human FRAXE mental retardation disorder, Lilli mutants in Drosophila and other mouse models of genes in this family.
 ...
PMID:FMR2 function: insight from a mouse knockout model. 1452 73

In an ongoing study human X chromosomal mental retardation genes (MRX) were mapped in the chicken genome. Up to now the homologs of 13 genes were localized by FISH techniques. Four genes from HSAXp (TM4SF2, RSK2/RPS6KA3, NLGN4, ARX) map to GGA1q13-->q31, and seven genes from HSAXq (OPHN1, AGTR2, ARHGEF6, PAK3, FACL4/ACS4, FMR2, ATRX) to GGA4p. The gene-rich region of HSAXq28 proved to be much less conserved. GDI1 localized to GGA1pter and SLC6A8 to a mid-sized microchromosome. The order of the genes was determined from the newly available genome sequence data from chicken, which reveals exact colinearity between the genes in HSAXp and GGA1q13-->q31, but completely scrambled gene order between the genes with common synteny from HSAXq and GGA4p. This result supports the hypothesis that the human X chromosome is a real ancient autosomal linkage group.
 ...
PMID:Localization of human X chromosomal mental retardation (MRX) genes in chicken and comparison with the chicken genome sequence data. 1562 55

Mental retardation is more common in males than females in the population, assumed to be due to mutations on the X chromosome. The prevalence of the 24 genes identified to date is low and less common than expansions in FMR1, which cause Fragile X syndrome. Systematic screening of all other X linked genes in X linked families with mental retardation is currently not feasible in a clinical setting. The phenotypes of genes causing syndromic and non-syndromic mental retardation (NLGN3, NLGN4, RPS6KA3(RSK2), OPHN1, ATRX, SLC6A8, ARX, SYN1, AGTR2, MECP2, PQBP1, SMCX, and SLC16A2) are first discussed, as these may be the focus of more targeted mutation analysis. Secondly, the relative prevalence of genes causing only non-syndromic mental retardation (IL1RAPL1, TM4SF2, ZNF41, FTSJ1, DLG3, FACL4, PAK3, ARHGEF6, FMR2, and GDI) is summarised. Thirdly, the problem of recurrence risk where a molecular genetics diagnosis has not been made and what proportion of the male excess of mental retardation is due to monogenic disorders of the X chromosome are discussed.
 ...
PMID:X linked mental retardation: a clinical guide. 1611 46

The devastating nature and lack of effective treatments associated with neurodegenerative diseases have stimulated a world-wide search for the elucidation of their molecular basis to which mouse models have made a major contribution. In combination with transgenic and knockout technologies, large-scale mouse mutagenesis is a powerful approach for the identification of new genes and associated signalling pathways controlling neuronal cell death and survival. Here we review the characterization of the robotic mouse, a novel model of autosomal dominant cerebellar ataxia isolated from an ENU-mutagenesis programme, which develops adult-onset region-specific Purkinje cell loss and cataracts, and displays defects in early T-cell maturation and general growth retardation. The mutated protein, Af4, is a member of the AF4/LAF4/FMR2 (ALF) family of putative transcription factors previously implicated in childhood leukaemia and FRAXE mental retardation. The mutation, which lies in a highly conserved region among the ALF family members, significantly reduces the binding affinity of Af4 to the E3 ubiquitin-ligase Siah-1a, isolated with Siah-2 as interacting proteins in the brain. This leads to a markedly slower turnover of mutant Af4 by the ubiquitin-proteasome pathway and consequently to its abnormal accumulation in the robotic mouse. Importantly, the conservation of the Siah-binding domain of Af4 in all other family members reveals that Siah-mediated proteasomal degradation is a common regulatory mechanism that controls the levels, and thereby the function, of the ALF family. The robotic mouse represents a unique model in which to study the newly revealed role of Af4 in the maintenance of vital functions of Purkinje cells in the cerebellum and further the understanding of its implication in lymphopoeisis.
 ...
PMID:The robotic mouse: unravelling the function of AF4 in the cerebellum. 1632 81

FRAXE fragile site associated mental retardation (FRAXE MR) belongs to a group of non-syndromic X-linked mental retardation. Two genes, FMR2 and FMR3 (likely a non-coding RNA) are transcribed from the FRAXE CpG island in the opposite directions. While the contribution of the FMR2 gene to FRAXE MR has been demonstrated, the role of the FMR3 gene is not known. We have screened 441 Brazilian mentally handicapped males for CCG repeat expansions in the FMR2 gene and identified a boy with a mutation (c.-414_-357del58) immediately distal to the FRAXE CCG repeat. We have established a skin fibroblast cell line from this patient and tested expression of both FMR2 and FMR3 genes. Reverse transcriptase PCR studies on the FMR2 and FMR3 genes showed that only the FMR3 gene transcription was abolished, suggesting a possible causal relationship between the lack of FMR3 expression and mental retardation in this patient. In the literature, there have been few deletions described near the FRAXE CCG repeat, but none was followed with expression studies. This is the first study showing missing expression in the FMR3 gene with normal FMR2 transcription leading to FRAXE mutation-likely phenotype. The FMR3 gene is likely a non-coding RNA gene. So far all individuals with FRAXE CCG repeat expansions and cytogenetically detectable FRAXE fragile site have both FMR2 and FMR3 gene expression abolished. Although the function of the FMR3 gene is not known, our present study together with previous studies on FRAXE MR suggest that it may play role in the processes underpinning normal learning and memory.
 ...
PMID:Lack of FMR3 expression in a male with non-syndromic mental retardation and a microdeletion immediately distal to FRAXE CCG repeat. 1646 43

AF4 gene, frequently translocated with mixed-lineage leukemia (MLL) in childhood acute leukemia, encodes a putative transcriptional activator of the AF4/LAF4/FMR2 (ALF) protein family previously implicated in lymphopoiesis and Purkinje cell function in the cerebellum. Here, we provide the first evidence for a direct role of AF4 in the regulation of transcriptional elongation by RNA polymerase II (Pol II). We demonstrate that mouse Af4 functions as a positive regulator of Pol II transcription elongation factor b (P-TEFb) kinase and, in complex with MLL fusion partners Af9, Enl and Af10, as a mediator of histone H3-K79 methylation by recruiting Dot1 to elongating Pol II. These pathways are interconnected and tightly regulated by the P-TEFb-dependent phosphorylation of Af4, Af9 and Enl which controls their transactivation activity and/or protein stability. Consistently, increased levels of phosphorylated Pol II and methylated H3-K79 are observed in the ataxic mouse mutant robotic, an over-expression model of Af4. Finally, we confirm the functional relevance of Af4, Enl and Af9 to the regulation of gene transcription as their over-expression strongly stimulates P-TEFb-dependent transcription of a luciferase reporter gene. Our findings uncover a central role for these proteins in the regulation of transcriptional elongation and coordinated histone methylation, providing valuable insight into their contribution to leukemogenesis and neurodegeneration. Since these activities likely extend to the entire ALF protein family, this study also significantly inputs our understanding of the molecular basis of FRAXE mental retardation syndrome in which FMR2 expression is silenced.
 ...
PMID:The mixed-lineage leukemia fusion partner AF4 stimulates RNA polymerase II transcriptional elongation and mediates coordinated chromatin remodeling. 1713 74

lilliputian (lilli), the sole Drosophila member of the FMR2/AF4 (Fragile X Mental Retardation/Acute Lymphoblastic Leukemia) family of transcription factors, is widely expressed with roles in segmentation, cellularization, and gastrulation during early embryogenesis with additional distinct roles at later stages of embryonic and postembryonic development. We identified lilli in a genetic screen based on the suppression of a lethal phenotype that is associated with ectopic expression of the transcription factor encoded by the segmentation gene runt in the blastoderm embryo. In contrast to other factors identified by this screen, lilli appears to have no role in mediating either the establishment or maintenance of engrailed (en) repression by Runt. Instead, we find that Lilli plays a critical role in the Runt-dependent activation of the pair-rule segmentation gene fushi-tarazu (ftz). The requirement for lilli is distinct from and temporally precedes the Runt-dependent activation of ftz that is mediated by the orphan nuclear receptor protein Ftz-F1. We further describe a role for lilli in the activation of Sex-lethal (Sxl), an early target of Runt in the sex determination pathway. However, lilli is not required for all targets that are activated by Runt and appears to have no role in activation of sloppy paired (slp1). Based on these results we suggest that Lilli plays an architectural role in facilitating transcriptional activation that depends both on the target gene and the developmental context.
 ...
PMID:The HMG-box protein Lilliputian is required for Runt-dependent activation of the pair-rule gene fushi-tarazu. 1713 70

Chromosomal microarray analysis (CMA) by array-based comparative genomic hybridization (CGH) is a new clinical test for the detection of well-characterized genomic disorders caused by chromosomal deletions and duplications that result in gene copy number variation (CNV). This powerful assay detects an abnormality in approximately 7-9% of patients with various clinical phenotypes, including mental retardation. We report here on the results found in a 6-year-old girl with mildly dysmorphic facies, obesity, and marked developmental delay. CMA was requested and showed a heterozygous loss in copy number with clones derived from the genomic region cytogenetically defined as Xq27.3-Xq28. This loss was not cytogenetically visible but was seen on FISH analysis with clones from the region. Further studies confirmed a loss of one copy each of the FMR1, FMR2, and IDS genes (which are mutated in Fragile X syndrome, FRAXE syndrome, and Hunter syndrome, respectively). Skewed X-inactivation has been previously reported in girls with deletions in this region and can lead to a combined Fragile X/Hunter syndrome phenotype in affected females. X-inactivation and iduronate 2-sulfatase (IDS) enzyme activity were therefore examined. X-inactivation was found to be random in the child's peripheral leukocytes, and IDS enzyme activity was approximately half of the normal value. This case demonstrates the utility of CMA both for detecting a submicroscopic chromosomal deletion and for suggesting further testing that could possibly lead to therapeutic options for patients with developmental delay.
 ...
PMID:Chromosomal microarray analysis (CMA) detects a large X chromosome deletion including FMR1, FMR2, and IDS in a female patient with mental retardation. 1750 8

Fragile X Syndrome is the most common form of hereditary mental retardation. It is caused by a large expansion of the CGG trinucleotide repeat (>200 repeats) in the 5'-untranslated region (UTR) of the FMR1 gene that leads to silencing of its transcript. Individuals with CGG repeat expansions approximately between 60 and 200 are referred to as premutation carriers. Fragile X-associated tremor and ataxia syndrome (FXTAS), an RNA-mediated neurodegenerative disease has been described in up to 50% of males carrying premutation alleles. FRAXE, the most common form of non-syndromic X-linked mental retardation, is caused by expansion of a CCG trinucleotide repeat (>200) in the 5'-UTR of the FMR2 gene. While the FRAXE premutation length repeat is observed in the general population, there has not yet been a report of a neurodegenerative phenotype associated with these alleles. In this study, we show that the CCG premutation length repeat leads to an RNA-mediated neurodegenerative phenotype in a Drosophila model. Furthermore, we show that co-expression of both the CCG and CGG-containing RNAs suppresses their independent toxicity and is dependent on the RNAi pathway. These data support the concept that RNA toxicity is the mechanism of neuronal toxicity and suggests potential reversal of RNA-mediated phenotypes with complementary RNA molecules.
 ...
PMID:Argonaute-2-dependent rescue of a Drosophila model of FXTAS by FRAXE premutation repeat. 1763 40

FRAXE is a form of mild to moderate mental retardation due to the silencing of the FMR2 gene. The cellular function of FMR2 protein is presently unknown. By analogy with its homologue AF4, FMR2 was supposed to have a role in transcriptional regulation, but robust evidences supporting this hypothesis are lacking. We observed that FMR2 co-localizes with the splicing factor SC35 in nuclear speckles, the nuclear regions where splicing factors are concentrated, assembled and modified. Similarly to what was reported for splicing factors, blocking splicing or transcription leads to the accumulation of FMR2 in enlarged, rounded speckles. FMR2 is also localized in the nucleolus when splicing is blocked. We show here that FMR2 is able to specifically bind the G-quartet-forming RNA structure with high affinity. Remarkably, in vivo, in the presence of FMR2, the ESE action of the G-quartet situated in mRNA of an alternatively spliced exon of a minigene or of the putative target FMR1 appears reduced. Interestingly, FMR1 is silenced in the fragile X syndrome, another form of mental retardation. All together, our findings strongly suggest that FMR2 is an RNA-binding protein, which might be involved in alternative splicing regulation through an interaction with G-quartet RNA structure.
 ...
PMID:FRAXE-associated mental retardation protein (FMR2) is an RNA-binding protein with high affinity for G-quartet RNA forming structure. 1913 66


<< Previous 1 2 3 4 5 Next >>