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)

Mutations in the MECP2 (methyl-CpG-binding protein 2) gene are known to cause Rett syndrome, a well-known and clinically defined neurodevelopmental disorder. Rett syndrome occurs almost exclusively in females and for a long time was thought to be an X-linked dominant condition lethal in hemizygous males. Since the discovery of the MECP2 gene as the cause of Rett syndrome in 1999, MECP2 mutations have, however, also been reported in males. These males phenotypically have classical Rett syndrome when the mutation arises as somatic mosaicism or when they have an extra X chromosome. In all other cases, males with MECP2 mutations show diverse phenotypes different from classical Rett syndrome. The spectrum ranges from severe congenital encephalopathy, mental retardation with various neurological symptoms, occasionally in association with psychiatric illness, to mild mental retardation only. We present a 21-year-old male with severe mental retardation, spastic tetraplegia, dystonia, apraxia and neurogenic scoliosis. A history of early hypotonia evolving into severe spasticity, slowing of head growth, breathing irregularities and good visual interactive behaviour were highly suggestive of Rett syndrome. He has a de novo missense mutation in exon 3 of the MECP2 gene (P225L). The clinical spectrum and molecular findings in males with MECP2 mutations are reviewed.
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PMID:Neurodevelopmental disorders in males related to the gene causing Rett syndrome in females (MECP2). 1261 69

RS, the most common cause of profound cognitive impairment in girls and women, is composed of characteristic clinical features, including communication dysfunction, stereotypic movements, and pervasive growth failure. Neuropathologic findings indicate a failure of neuronal maturation with too small neurons and too few dendritic arbors and no evidence of a progressive neurodegenerative process. The combination of clinical and neuropathologic characteristics presents the profile of a neurodevelopmental disorder. Mutations in the gene MECP2, which encodes MeCP2, have been identified in 80% to 85% of girls and women with RS. Furthermore, the panorama of phenotypes with MECP2 mutations now extends far beyond RS to include normal girls and women, mild learning disability, autistic spectrum disorders, and X-linked mental retardation. These rapid advances in our understanding of RS over the past three decades have opened new avenues of study in developmental neurobiology.
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PMID:Rett syndrome. Current status and new vistas. 1261 84

A female patient with non-syndromic mental retardation was shown by high resolution GTL banding to have inherited an apparently balanced translocation, 46,X,t(X;8)(q28;q12)mat. Replication studies in the mother and daughter showed a skewed X inactivation pattern in lymphocytes, with the normal X chromosome preferentially inactivated. The mother also had significant intellectual disability. To investigate the possibility that a novel candidate gene for XLMR was disrupted at the X chromosome translocation breakpoint, we mapped the breakpoint using fluorescence in situ hybridisation (FISH). This showed that the four known genes involved in non-syndromic mental retardation in Xq28, FMR2, SLC6A8, MECP2, and GDI1, were not involved in the translocation. Intriguingly, we found that the X chromosome breakpoint in the daughter could not be defined by a single breakpoint spanning genomic clone and further analysis showed a 650 kb submicroscopic duplication between DXS7067 and DXS7060 on either side of the X chromosome translocation breakpoint. This duplicated region contains 11 characterised genes, of which nine are expressed in brain. Duplication of one or several of the genes within the 650 kb interval is likely to be responsible for the mental retardation phenotype seen in our patient. Xq28 appears to be an unstable region of the human genome and genomic rearrangements are recognised as major causes of two single gene defects, haemophilia A and incontinentia pigmenti, which map within Xq28. This patient therefore provides further evidence for the instability of this genomic region.
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PMID:Identification of a 650 kb duplication at the X chromosome breakpoint in a patient with 46,X,t(X;8)(q28;q12) and non-syndromic mental retardation. 1262 34

Rett syndrome (RTT) is a severe neurodevelopmental disorder affecting almost exclusively girls. It is currently considered a monogenic X-linked dominant disorder due to mutations in MECP2 gene, encoding the methyl-CpG binding protein 2. A few RTT male cases, resulting from mosaicism for MECP2 mutations, have been reported. Male germline MECP2 mutations cause either severe encephalopathy with death at birth (usually in brothers of classical RTT females) or X-linked recessive mental retardation (XLMR). To date the wide phenotypic heterogeneity associated with MECP2 mutations in females (from classical RTT to healthy carriers) has been explained by differences in X chromosome inactivation. However, conflicting results have been obtained in different studies, with both random and highly skewed X-inactivation reported in healthy carrier females. Consequently it is possible that mechanisms other than X-inactivation play a role in the expressivity of MECP2 mutations. To explain the phenotypic heterogeneity associated with MECP2 mutations we propose a digenic model in which the presence of a "mutated" allele in a second gene, leading to a less functional protein, determines the clinical severity of the MECP2 mutation. The model is supported by the identification of the same mutation in XLMR and RTT cases. The carrier mothers of XLMR families are clinically asymptomatic and present balanced X chromosome inactivation. Therefore the same mutation arising in different genetic backgrounds can cause XLMR in males, remain silent in the carrier females and cause classic RTT in females. MECP2 mutations account for approximately 70-80% of classic RTT cases. MECP2 negative cases might result from mutations in noncoding regions of MECP2 gene. Alternatively, these cases might be due to mutations in other genes (locus heterogeneity). This hypothesis is supported by the identification of several chromosomal rearrangements in MECP2 negative patients with RTT and RTT-like phenotypes. MeCP2 is considered a general transcriptional repressor. However, conditional mouse mutants with selective loss of Mecp2 in the brain develop clinical manifestations similar to RTT, indicating that MECP2 is exclusively required for central nervous system function. The involvement of MeCP2 in methylation-specific transcriptional repression suggests that MECP2 related disorders result from dysregulated gene expression. Studies on gene expression have been performed in mouse and human brains. A relatively small number of gene expression changes were identified. It is possible that MeCP2 causes dysregulation of a very small subset of genes that are not detected with this method of analysis, or that very subtle changes in many genes cause the neuronal phenotype.
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PMID:Rett syndrome: the complex nature of a monogenic disease. 1275 Aug 21

Mental retardation (MR) is a symptom in a large group of clinical conditions and affects around 3% of the population. MR is divided into syndromic, if it is characterized by distinctive clinical features and nonspecific when mental retardation is the only defining manifestation. Although genetic causes of X-linked mental retardation (XLMR) are heterogenous and complex, recent findings have led to the identification of an increasing number of genes involved in these conditions. Eight genes involved in nonspecific X-linked mental retardation have been identified so far, including FMR2, GDI1, OPHN1, PAK3, ARHGEF6, IL1RAPL, TM4SF2, and FACL4. Four other MECP2, RSK2, ARX, ATR-X are involved in syndromic and nonspecific forms of MR. Recent research has shown that these genes encode for proteins involved in signaling pathways which regulate cytoskeleton organization, synaptic vesicle transport and establishment of connections between neuronal cells. These findings provide insight into the molecular mechanisms of crucial processes for the development of intellectual and cognitive functions.
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PMID:[Monogenic causes of nonspecific X-linked mental retardation molecular aspects]. 1281 Sep 81

Rett syndrome is a neurodevelopmental disorder with severe mental retardation caused by mutations in the MECP2 gene. Mutations in the MECP2 gene are also associated with other genetic disorders, including X linked mental retardation in males. Missense mutations identified so far are present primarily in the methyl CpG binding domain (MBD) of MECP2. Here, the functional significance of 28 MBD missense mutations identified in patients were analysed by transient expression of the mutant proteins in cultured cells. The effects of mutations were evaluated by analysis of the affinity of MeCP2 to pericentromeric heterochromatin in mouse L929 cells and on transcriptional repressive activity of MeCP2 in Drosophila SL2 cells. These analyses showed that approximately one-third (9/28) of MBD missense mutations showed strong impairment of MeCP2 function. The mutation of the R111 residue, which directly interacts with the methyl group of methyl cytosine, completely abolished MeCP2 function and mutations affecting beta-sheets and a hairpin loop have substantial functional consequences. In contrast, mutations that showed marginal or mild impairment of the function fell in unstructured regions with no DNA interaction. Since each of these mutations is known to be pathogenic, the mutations may indicate residues that are important for specific functions of MeCP2 in neurones.
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PMID:Heterogeneity in residual function of MeCP2 carrying missense mutations in the methyl CpG binding domain. 1284 18

OBJECTIVE: To discuss clinical and electroencephalographic aspects and the genetic mechanisms of three neurogenic syndromes that can be related to nosologic entities in the heterogenic pathological group presenting symptoms of mental retardation and autism. SOURCES: The authors carried out a bibliographic review on each syndrome involved, correlating and characterizing the neurological manifestations, as well as describing genetic mechanisms and identifying biological markers. SUMMARY OF THE FINDINGS: The authors were able to confirm that Rett Sydrome is a genetic disease resulting from the mutation of the MECP2 gene and clinical variations can be explained by different mutations in this gene. Angelman syndrome has four genetic mechanisms responsible for phenotypic variations and different risks of recurrence. In Fragile-X syndrome, the degree of cognitive impairment is related to the number of trinucleotide repeats. CONCLUSIONS: Different genetic mechanisms of the three syndromes are responsible for clinical variability. By identifying the biological markers, the diagnosis will be performed earlier and it will be possible to identify new subtle expressions of the disease.
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PMID:[Neurological manifestation and genetic diagnosis of Angelman, Rett and Fragile-X syndromes] 1467 69

Angelman syndrome (AS) is an imprinted neurobehavioral disorder characterized by mental retardation, absent speech, excessive laughter, seizures, ataxia, and a characteristic EEG pattern. Classical lesions, including deletion, paternal disomy, or epigenetic mutation, are confirmatory of AS diagnoses in 80% of cases. Loss-of-function mutations of the UBE3A gene have been identified in approximately 8% of AS cases, failing to account for the remaining patient population, and there appears to be a higher prevalence of mutations in familial than sporadic cases. We screened UBE3A in 45 index cases of AS without obvious 15q11-13 abnormalities. Pathological mutations were identified in 3/6 (50%) familial and 4/39 (>10%) sporadic cases. By combining our data with those of the literature, we demonstrate statistically that the frequency of UBE3A mutations is significantly higher in the familial than sporadic subsets of AS. This indicates that an independent molecular mechanism or 'phenocopy' exists for the sporadic group. Rett syndrome (RS), caused by mutations of the MECP2 gene, and patients with deletions of 22q13.3 --> qter, have overlapping clinical features with AS. We screened 24 of the sporadic AS cases without detectable UBE3A mutations for mutations of MECP2, but found none. A separate cohort of 43 atypical patients with features common to AS and RS, in whom 15q11-13 lesions and 22q13.3 --> qter deletion had been ruled out, were also screened for MECP2 mutations. One male patient was mosaic for a frameshift mutation of this gene (previously reported). While MECP2 mutations can cause a phenotype reminiscent of AS in rare cases, they fail to account for the excess of sporadic patients with a definitive clinical diagnosis of AS.
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PMID:Investigation of UBE3A and MECP2 in Angelman syndrome (AS) and patients with features of AS. 1498 18

MeCP2 is the founder member of a family of methyl-CpG-binding proteins able to repress transcription from methylated DNA. To date, MeCP2 action seems to involve the delivery on modified DNA of histone deacetylase activity, followed by histone methylating activity. It has been recently demonstrated that MECP2 mutations cause Rett syndrome, a childhood neurological disorder that represents one of the most common causes of mental retardation in females. Here we show that a novel Xenopus laevis protein of 20 kDa, p20, is able to interact in vivo and in vitro with MeCP2. The p20 sequence revealed that it belongs to the family of the WAP (whey acidic protein) proteins, often functioning as a protease inhibitor. Therefore, we asked whether the p20 can influence the MeCP2 half-life. We demonstrate that, indeed, the xp20 not only can significantly increase the stability of an exogenously expressed MeCP2 in Xenopus oocytes but also can stabilize the human endogenous MeCP2. The capability of the mammalian methyl-CpG-binding protein to interact with p20 is confirmed by co-immunoprecipitation experiments performed overexpressing the WAP protein. Glutathione S-transferase pull-down assays reveal that the MeCP2 residues localized between the methyl-binding domain and the transcriptional repression domain is the primary interaction surface. Our data suggest that regulation of MeCP2 metabolism might be of relevant importance; in accordance with this, previous results have shown that some Rett syndrome mutations are characterized by a decrease in MeCP2 stability.
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PMID:A novel protein, Xenopus p20, influences the stability of MeCP2 through direct interaction. 1505 64

Rett syndrome, one of the leading causes of mental retardation and developmental regression in girls, is the first pervasive developmental disorder with a known genetic cause. The majority of cases of sporadic Rett syndrome are caused by mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2). MeCP2 binds methylated DNA and likely regulates gene expression and chromatin structure. Genotype/phenotype analysis revealed that the phenotypic spectrum of MECP2 mutations in humans is broader than initially suspected: Mutations have been discovered in Rett syndrome variants, mentally retarded males, and autistic children. A variety of in vivo and in vitro models has been developed that allow analysis of MeCP2 function and pathogenic studies of Rett syndrome. Because the neuropathology of Rett syndrome shares certain features with other neurodevelopmental disorders, a common pathogenic process may underlie these disorders. Thus, Rett syndrome is a prototype for the genetic, molecular, and neurobiological analysis of neurodevelopmental disorders.
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PMID:Rett syndrome: a prototypical neurodevelopmental disorder. 1507 Apr 86


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