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)

Many syndromes associated with mental retardation (MR) are characterized by cortical dendritic anomalies. Despite their morphological similarity, these changes appear to involve different stages of dendritic development. The neuronal cytoskeleton, which includes microfilaments, neurofilaments and microtubules, is essential for these developmental processes. Levels and phosphorylation of microtubule-associated proteins (MAPs), which stabilize microtubules, seem to determine different stages of dendritic formation with certain MAPs (e.g. MAP-2) appearing to mediate the effects of external modulators upon these processes. Early studies on neuronal cytoskeleton in MR, which have shown a selective reduction in MAP-2 expression, have focused on Rett syndrome (RS). Here, by a semiquantitative immunohistochemical analysis of the pericentral cortex, we examine the contribution of specific neuronal populations to these changes in cytoskeletal proteins. Decreased MAP-2 staining in RS was more marked in layers V-VI, while increased nonphosphorylated neurofilament immunoreactivity was found in layers II-III in RS. Age-related increases in dendritic MAP-2 immunoreactivity in layers V-VI were also absent in RS. The specificity of these cytoskeletal protein changes, their significance for RS pathogenesis and plasticity, as well as their implications for other MR-associated disorders, are also discussed.
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PMID:Dendritic cytoskeletal protein expression in mental retardation: an immunohistochemical study of the neocortex in Rett syndrome. 1100 50

In contrast to the preponderance of affected males in families with X-linked mental retardation, Rett syndrome (RTT) is a neurological disorder occurring almost exclusively in females. The near complete absence of affected males in RTT families has been explained by the lethal effect of an X-linked gene mutation in hemizygous affected males. We report here on a novel mutation (A140V) in the MECP2 gene detected in one female with mild mental retardation. In a family study, the A140V mutation was found to segregate in the affected daughter and in four adult sons with severe mental retardation. These results indicate that MECP2 mutations are not necessarily lethal in males and that they can be causative of non-specific X-linked mental retardation.
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PMID:MECP2 mutation in male patients with non-specific X-linked mental retardation. 1100 80

Rett syndrome (RTT) is an X-linked dominant neurodevelopmental disorder that manifests in females, typically after the first year of life. It is a leading cause of mental retardation and autistic behavior in girls and women; a hallmark of the disease is incessant hand movements in the form of wringing, twisting, or clapping. It was recently discovered that RTT is caused by mutations in the methyl-CpG-binding protein 2 (MECP2) gene. MECP2 assists in the transcriptional silencing process via DNA methylation; we hypothesize that disruption of this gene alters the normal developmental expression of various other genes, some of which must account for the peculiar neurologic phenotype of RTT. Molecular studies have identified MECP2 mutations in up to 80% of classic RTT patients; mutation type has some effect on the phenotypic manifestation of RTT, but the pattern of X inactivation seems to determine phenotypic severity. Favorable (skewed) X inactivation can so spare a patient from the effects of mutant MECP2 that they display only the mildest learning disability or no phenotype at all. The unmitigated impact of mutant MECP2 can be inferred from the few males who have been born into RTT kindreds with such severe neonatal encephalopathy that they did not survive their second year. MECP2 mutations thus manifest in a far broader array of phenotypes than classic RTT. This discovery should prove helpful in diagnosing cases of mild learning disability or severe neonatal encephalopathies of unknown cause and also should provide insight into the pathogenesis of RTT.
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PMID:Rett syndrome: methyl-CpG-binding protein 2 mutations and phenotype-genotype correlations. 1118 Feb 22

Mecp2 is an X-linked gene encoding a nuclear protein that binds specifically to methylated DNA (ref. 1) and functions as a general transcriptional repressor by associating with chromatin-remodeling complexes. Mecp2 is expressed at high levels in the postnatal brain, indicating that methylation-dependent regulation of gene expression may have a crucial role in the mammalian central nervous system. Consistent with this notion is the recent demonstration that MECP2 mutations cause Rett syndrome (RTT, MIM 312750), a childhood neurological disorder that represents one of the most common causes of mental retardation in females. Here we show that Mecp2-deficient mice exhibit phenotypes that resemble some of the symptoms of RTT patients. Mecp2-null mice were normal until 5 weeks of age, when they began to develop disease, leading to death between 6 and 12 weeks. Mutant brains showed substantial reduction in both weight and neuronal cell size, but no obvious structural defects or signs of neurodegeneration. Brain-specific deletion of Mecp2 at embryonic day (E) 12 resulted in a phenotype identical to that of the null mutation, indicating that the phenotype is caused by Mecp2 deficiency in the CNS rather than in peripheral tissues. Deletion of Mecp2 in postnatal CNS neurons led to a similar neuronal phenotype, although at a later age. Our results indicate that the role of Mecp2 is not restricted to the immature brain, but becomes critical in mature neurons. Mecp2 deficiency in these neurons is sufficient to cause neuronal dysfunction with symptomatic manifestation similar to Rett syndrome.
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PMID:Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice. 1124 18

Rett syndrome, a neurodevelopmental disorder that is a leading cause of mental retardation in females, is caused by mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MeCP2). MECP2 mutations have subsequently been identified in patients with a variety of clinical syndromes ranging from mild learning disability in females to severe mental retardation, seizures, ataxia, and sometimes neonatal encephalopathy in males. In classic Rett syndrome, genotype-phenotype correlation studies suggest that X chromosome inactivation patterns have a more prominent effect on clinical severity than the type of mutation. When the full range of phenotypes associated with MECP2 mutations is considered, however, the mutation type strongly affects disease severity. MeCP2 is a transcriptional repressor that binds to methylated CpG dinucleotides throughout the genome, and mutations in Rett syndrome patients are thought to result in at least a partial loss of function. Abnormal gene expression may thus underlie the phenotype. Discovering which genes are misregulated in the absence of functional MeCP2 is crucial for understanding the pathogenesis of this disorder and related syndromes.
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PMID:Molecular genetics of Rett syndrome and clinical spectrum of MECP2 mutations. 1126 31

Following the recent discovery that the methyl-CpG binding protein 2 (MECP2) gene located on Xq28 is involved in Rett syndrome (RTT), a wild spectrum of phenotypes, including mental handicap, has been shown to be associated with mutations in MECP2. These findings, with the compelling genetic evidence suggesting the presence in Xq28 of additional genes besides RabGDI1 and FMR2 involved in non-specific X-linked mental retardation (MRX), prompted us to investigate MECP2 in MRX families. Two novel mutations, not found in RTT, were identified. The first mutation, an E137G, was identified in the MRX16 family, and the second, R167W, was identified in a new mental retardation (MR) family shown to be linked to Xq28. In view of these data, we screened MECP2 in a cohort of 185 patients found negative for the expansions across the FRAXA CGG repeat and reported the identification of mutations in four sporadic cases of MR. One of the mutations, A140V, which we found in two patients, has been described previously, whereas the two others, P399L and R453Q, are novel mutations. In addition to the results demonstrating the involvement of MECP2 in MRX, this study shows that the frequency of mutations in MECP2 in the mentally retarded population screened for the fragile X syndrome is comparable to the frequency of the CGG expansions in FMR1. Therefore, implementation of systematic screening of MECP2 in MR patients should result in significant progress in the field of molecular diagnosis and genetic counseling of mental handicap.
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PMID:MECP2 is highly mutated in X-linked mental retardation. 1130 67

Methylation of genomic CpG residues is crucial for proper neuronal function. Rett syndrome, a common form of mental retardation, is associated with mutations in the gene encoding MeCP2, a methyl CpG binding protein linked to transcriptional repression. Gene knockouts of mouse Mecp2 have reproduced key aspects of the disease. A CNS-restricted knockout of Dnmt1, encoding the enzyme that maintains CpG methylation patterns, results in loss of mutant neurons and glia.
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PMID:Methylated cytosine and the brain: a new base for neuroscience. 1143 Jul 98

Autistic disorder is a pervasive developmental disorder considered to have a multigenic origin. Mental retardation is present in 75% of autistic patients. Autistic features are found in Rett syndrome, a neurological disorder affecting girls and associated with severe mental retardation. Recently, the gene responsible for the Rett syndrome, methyl CpG-binding protein (MECP2) gene, was identified on the X chromosome by a candidate gene strategy. Mutations in this gene were also observed in some mentally retarded males. In this study we tested MECP2 as a candidate gene in autistic disorder by a DGGE analysis of its coding region and intron-exon boundaries. Among 59 autistic patients, 42 males and 17 females, mentally retarded or not, no mutations or polymorphisms were present in the MECP2 gene. Taking into account the size of our sample, we conclude that MECP2 coding sequence mutations are not an important factor (less than 5% of cases) in the aetiology of autistic disorder.
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PMID:No mutations in the coding region of the Rett syndrome gene MECP2 in 59 autistic patients. 1146 49

Dysfunction of the prefrontal cortex may contribute to the autistic features and mental retardation of Rett syndrome, a neuropsychiatric condition caused by mutations of the gene encoding methyl-CpG-binding protein 2 (MeCP2). Because nothing is known about the expression of MeCP2 and other chromatin-associated factors in primate brain, we studied in monkey prefrontal cortex and murine cerebral cortex expression patterns of MeCP2 and of macrohistone H2A (MacroH2A), which like MeCP2 is associated with transcriptionally silent chromatin. In both species, MeCP2 and MacroH2A appeared to be ubiquitously expressed by cortical neurons, including projection neurons and GABAergic interneurons. In the adult monkey, MeCP2 expression was robust throughout all layers of the prefrontal cortex but it was limited in fetal monkeys at embryonic day 110 to the deeper cortical layers and the subplate. These results suggest that MeCP2 may be important for neuronal maintenance in the developing and in the mature primate prefrontal cortex, consistent with the previously reported phenotype of MeCP2-null mutant mice.
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PMID:Expression pattern of the Rett syndrome gene MeCP2 in primate prefrontal cortex. 1159 48

Recent studies have demonstrated that biogenic amines have a function of facilitating formation and maintenance of synapses in diverse regions of the central nervous system in developing and adult animals. The normal number of synapses maintained by biogenic amines are crucial to acquire learning and memory. The level of biogenic amines was reported to decrease in the brain by several neurodevelopmental disorders associated with mental retardation and developmental disabilities such as Rett syndrome, autism and Down syndrome. Taken into consideration this fact together with the function of biogenic amines for synapses, the density of synapses appears to decrease considerably in the brains of patients suffered from the neurodevelopmental disorders. The synaptic overproduction during the critical period of development especially 1 year after birth has been considered as a background mechanism to provide plasticity for the developing brain. Synaptic overproduction does not appear to occur in the brains of patients suffered from the neurodevelopmental disorders, which they are observed mental retardation occurring in the first 1 year after birth. Along with the neurodevelopmental disorders, environmental factors (stress, drugs and nutrition) during pre- and post-natal critical developmental periods are known to change levels of biogenic amines in the brain. In fact, maternal stress has been shown to decrease the levels of serotonin and the density of synapses in the hippocampus of the offspring, and they showed developmental disabilities in the spatial learning and memory. A cascade appears to exist from either the child neurological disorders or the environmental factors to mental retardation and developmental disabilities by decreases in the levels of biogenic amines and synaptic density.
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PMID:A biogenic amine-synapse mechanism for mental retardation and developmental disabilities. 1173 35


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