Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rett syndrome (RTT) is an X-linked disorder caused by mutations in the methyl CpG binding protein 2 (MECP2) gene. The pattern of X-chromosome inactivation (XCI) is thought to play a role in phenotypic severity. In the present study, patterns of XCI were assessed by lacZ staining of embryos and adult brains of mice heterozygous for a X-linked Hmgcr-nls-lacZ transgene on a mutant mouse model of RTT. We found that there was no difference between the lacZ staining patterns in the brain of wild-type and heterozygous mutant embryos at embryonic day 9.5 (E9.5) suggesting that Mecp2 has no effect on the primary pattern of XCI. At 20 weeks of age, there was no significant difference between XCI patterns in the Purkinje cells in the cerebellum of heterozygous mutant and wild-type mice when the mutant allele was inherited from the mother. However, when the mutant allele was paternally inherited, a significant difference was detected. Thus, parental origin of the mutation may have a bearing on phenotype through XCI patterns. An estimation of the Purkinje cell precursor number based on XCI mosaicism revealed that, when the mutation was paternally inherited, the precursor number was less than that in the wild-type mice. Therefore, it is likely that the number of precursor cells allocated to the Purkinje cell lineage is affected by a paternally inherited mutation in Mecp2. We also observed that the pattern of XCI in cultured fibroblasts was significantly correlated with patterns in the Purkinje cells in mutant animals but not in wild-type mice.
Hum Mol Genet 2005 Jul 01
PMID:Reduced proportion of Purkinje cells expressing paternally derived mutant Mecp2308 allele in female mouse cerebellum is not due to a skewed primary pattern of X-chromosome inactivation. 1588 76

Rett syndrome (RTT) is a severe neurodevelopmental disorder almost exclusively affecting females and characterized by a wide spectrum of clinical manifestations. Most patients affected by classic RTT and a smaller percentage of patients with the milder form 'preserved speech variant' have either point mutations or deletions/duplications in the MECP2 gene. Recently, mutations in the CDKL5 gene, coding for a putative kinase, have been found in female patients with a phenotype overlapping with that of RTT. Here, we report two patients with the early seizure variant of RTT, bearing two novel CDKL5 truncating mutations, strengthening the correlation between CDKL5 and RTT. Considering the similar phenotypes caused by mutations in MECP2 and CDKL5, it has been suggested that the two genes play a role in common pathogenic processes. We show here that CDKL5 is a nuclear protein whose expression in the nervous system overlaps with that of MeCP2, during neural maturation and synaptogenesis. Importantly, we demonstrate that MeCP2 and CDKL5 interact both in vivo and in vitro and that CDKL5 is indeed a kinase, which is able to phosphorylate itself and to mediate MeCP2 phosphorylation, suggesting that they belong to the same molecular pathway. Furthermore, this paper contributes to the clarification of the phenotype associated with CDKL5 mutations and indicates that CDKL5 should be analyzed in each patient showing a clinical course similar to RTT but characterized by a lack of an early normal period due to the presence of seizures.
Hum Mol Genet 2005 Jul 15
PMID:CDKL5 belongs to the same molecular pathway of MeCP2 and it is responsible for the early-onset seizure variant of Rett syndrome. 1591 71

Rett syndrome (RTT) is a severe form of mental retardation, which is caused by spontaneous mutations in the X-linked gene MECP2. How the loss of MeCP2 function leads to RTT is currently unknown. Mice lacking the Mecp2 gene initially show normal postnatal development but later acquire neurological phenotypes, including heightened anxiety, that resemble RTT. The MECP2 gene encodes a methyl-CpG-binding protein that can act as a transcriptional repressor. Using cDNA microarrays, we found that Mecp2-null animals differentially express several genes that are induced during the stress response by glucocorticoids. Increased levels of mRNAs for serum glucocorticoid-inducible kinase 1 (Sgk) and FK506-binding protein 51 (Fkbp5) were observed before and after onset of neurological symptoms, but plasma glucocorticoid was not significantly elevated in Mecp2-null mice. MeCP2 is bound to the Fkbp5 and Sgk genes in brain and may function as a modulator of glucocorticoid-inducible gene expression. Given the known deleterious effect of glucocorticoid exposure on brain development, our data raise the possibility that disruption of MeCP2-dependent regulation of stress-responsive genes contributes to the symptoms of RTT.
Hum Mol Genet 2005 Aug 01
PMID:Up-regulation of glucocorticoid-regulated genes in a mouse model of Rett syndrome. 1600 17

DNA methylation is interpreted by a family of methyl-CpG binding domain (MBD) proteins that repress transcription through recruitment of corepressors that modify chromatin. To compare in vivo binding of MeCP2 and MBD2, we analyzed immunoprecipitated chromatin from primary human cells. Genomic sites occupied by the two MBD proteins were mutually exclusive. As MeCP2 was unable to colonize sites vacated by depletion of MBD2, we tested the hypothesis that methyl-CpG alone is insufficient to direct MeCP2 binding. In vitro selection for MeCP2 bound DNA-enriched fragments containing A/T bases ([A/T] > or = 4) adjacent to methyl-CpG. [A/T] > or = 4 was found to be essential for high-affinity binding at selected sites and at known MeCP2 target regions in the Bdnf and Dlx6 genes. MBD2 binding, however, did not require an A/T run. The unexpected restriction of MeCP2 to a defined subset of methyl-CpG sites will facilitate identification of genomic targets that are relevant to Rett Syndrome.
Mol Cell 2005 Sep 02
PMID:DNA binding selectivity of MeCP2 due to a requirement for A/T sequences adjacent to methyl-CpG. 1613 22

A lymphotoxin-beta (LT-beta) gene has been cloned and sequenced in rainbow trout and provides the first conclusive evidence for the existence of LT-beta in teleost. Two isoforms of LT-beta were isolated. LT-beta1 cDNA was composed of 952 bp (with a 139 bp 5'-UTR and a 201 bp 3'-UTR) and LT-beta2 cDNA was 836 bp (with a 237 bp 5'-UTR and a 197 bp 3'-UTR) both of which translated into a protein of 203 amino acid residues. Both isoforms contained a predicted transmembrane domain of 21 amino acid residues (Leu11-Val31) and the TNF family signature (Val104-Phe120). Homology and phylogenetic analysis of trout LT-beta's with other known TNF family member showed good similarity to TNF-N (teleost) and other LT-beta (mammals and frog). LT-beta1 and TNF-alpha (1 and 2) genes were highly expressed in unstimulated trout head kidney, spleen, gill and intestine, whereas LT-beta2 was weakly expressed only in the gill. The expression of LT-beta1 and -beta2 genes was not found in macrophage (RTS-11) and fibroblast (RTG-2) like cell lines, although the TNF-alpha2 gene was expressed in both cell lines with the TNF-alpha1 gene only expressed in RTS-11 cells. In head kidney cells, expression of LT-beta1 and TNF-alpha (1, 2) genes was increased by stimulation with PHA or LPS. The discovery of trout LT-beta will allow a more complete analysis of fish inflammatory responses.
Mol Immunol 2006 Mar
PMID:Identification and expression analysis of lymphotoxin-beta like homologues in rainbow trout Oncorhynchus mykiss. 1614 8

Rett syndrome (RTT) is caused by mutations in the gene encoding methyl CpG-binding protein 2 (MeCP2). Although MeCP2 shows widespread expression in both neuronal and non-neuronal tissues, the symptoms of RTT are largely neurological. Herein, we have identified the regulatory region of the mouse Mecp2 gene that is sufficient for its restricted expression in neurons. A segment of the Mecp2 gene (-677/+56) exhibited strong promoter activity in neuronal cell lines and cortical neurons, but was inactive in non-neuronal cells and glia. The region necessary for neuronal-specific promoter activity was located within a 19 bp region (-63/-45). Several nuclear factors were found to bind to this region and some of these factors were enriched in nuclear extracts prepared from the brain. To examine the activity of the Mecp2 promoter in vivo, we generated transgenic mice expressing the LacZ reporter driven by the -677/+56 region of the Mecp2 gene. The transgene was expressed in the mesencephalon as early as embryonic day 10 and in the hindbrain and spinal cord by E12. Interestingly, a marked induction of transgene expression was observed postnatally throughout the brain, similar to that of endogenous MeCP2. However, expression of the transgene was absent in non-neuronal tissues that are known to express Mecp2. Taken together, these data indicate that the -677/+56 region of the Mecp2 promoter partially recapitulates the native expression pattern of the Mecp2 gene, which possesses restricted expression in neurons of the central nervous system.
Hum Mol Genet 2005 Dec 01
PMID:A segment of the Mecp2 promoter is sufficient to drive expression in neurons. 1625 Nov 99

X-linked cyclin-dependent kinase-like 5 (CDKL5 or STK9) has recently been implicated in atypical Rett and X-linked West syndromes, severe neurological disorders associated with mental retardation, loss of communication and motor skills and infantile spasms and seizures in predominantly females. Besides CDKL5, these disease phenotypes are also linked to mutations in the MECP2 and ARX genes. Here, we have expressed and characterized CDKL5 and its mutant forms. CDKL5 is a 118 kDa protein that is widely distributed in all tissues, with highest levels in brain, thymus and testes. Whole mount embryo staining reveals CDKL5 to be ubiquitous. Within cells, CDKL5 is localized primarily in the nucleus. Removal of the C-terminal domain increases CDKL5 expression, enhances autophosphorylation activity and causes perinuclear localization, indicating that the C-terminus regulates CDKL5 function. Although we detect MeCP2 but not ARX binding to CDKL5, our results suggest that neither of these proteins are direct substrates of the CDKL5 kinase. Finally, the CDKL5 mutations associated with the disease phenotype cause loss of kinase activity as assessed by autophosphorylation. These results suggest that inactivation of the CDKL5 kinase can lead to severe neurodevelopmental disorders.
Hum Mol Genet 2005 Dec 15
PMID:CDKL5/Stk9 kinase inactivation is associated with neuronal developmental disorders. 1633 Apr 82

Rett syndrome (RTT) is an X-linked dominant disabling neurodevelopmental disorder caused by loss of function mutations in the MECP2 gene, located at Xq28, which encodes a multifunctional protein. MECP2 expression is regulated in a developmental stage and cell-type-specific manner. The need for tightly controlled MeCP2 levels in brain is strongly suggested by neurologically abnormal phenotypes of mouse models with mild overexpression and by mental retardation in human males with MECP2 duplication. We set out to identify long-range cis-regulatory sequences that differentially regulate MECP2 transcription and, when mutated, may contribute to the pathogenesis of RTT, autism or X-linked mental retardation. By inter-species sequence comparisons, we detected 27 highly conserved non-coding DNA sequences within a 210 kb region covering MECP2. We functionally confirmed four enhancer and two silencer elements by performing luciferase reporter assays in four different human cell lines. The transcription factor binding capability of the identified regulatory elements was tested by gel shift assays. To locate the human MECP2 core promoter, we dissected the promoter region by reporter assays with deletion constructs. We then used chromosome conformation capture methods to document long-range interactions of three enhancers and two silencers with the MECP2 promoter. Acting over distances of up to 130 kb, these elements may influence chromatin configurations and regulate MECP2 transcription. Our study has defined the "MECP2 functional expression module" and identified enhancer and silencer elements that are likely to be responsible for the tissue-specific, developmental stage-specific or splice-variant-specific control of MeCP2 protein expression.
Hum Mol Genet 2006 Jun 01
PMID:Identification of cis-regulatory elements for MECP2 expression. 1661

Once bound to methylated CpG sites, methyl-CpG-binding protein 2 (MeCP2) is thought to silence transcription of downstream genes by recruiting a histone deacetylase (HDAC). Mutations within the MeCP2 gene have been found to cause Rett syndrome, a disorder of arrested neuronal development. Using immunohistochemistry, we found that Mecp2, as well as the methyl-CpG-binding protein MBD1, were significantly induced in normal adult rat brain after repeated injections of fluoxetine or cocaine for 10 days (one injection per day). Mecp2 was not induced by repeated injections of 1-(2-bis(4-fluorphenyl)-methoxy)-ethyl)-4-(3-phenyl-propyl)piperazine (GBR-12909) or nortriptyline. Together, the data indicate that the serotonergic system is predominantly involved. Using real-time reverse transcription-polymerase chain reaction experiments, MBD1 mRNA and both Mecp2_e1 and Mecp2_e2 transcripts were found to be induced by fluoxetine. Induction of the methylbinding proteins was accompanied with enhanced HDAC2 labeling intensity and mRNA synthesis in response to fluoxetine. In tandem, acetylated forms of histone H3 were found to be decreased. The effect was characterized in three serotonin projection areas, the caudate-putamen, the frontal cortex, and the dentate gyrus subregion of hippocampus. Our data highlight GABAergic neurons as major target cells expressing Mecp2 in response to the serotonin-elevating agents and suggest that serotonin signaling enhances gene silencing in postmitotic neurons.
Mol Pharmacol 2006 Aug
PMID:Fluoxetine and cocaine induce the epigenetic factors MeCP2 and MBD1 in adult rat brain. 1672 45

Rett syndrome (RTT) is an X-linked dominant neurodevelopmental disorder affecting 1 per 10,000-15,000 female births worldwide. The disease-causing gene has been identified as MECP2 (methyl-CpG-binding protein 2). In this study, we performed diagnostic mutational analysis of the MECP2 gene in RTT patients. Four exons and a putative promoter of the MECP2 gene were analyzed from the peripheral blood of 43 Korean patients with Rett syndrome by PCR-RFLP and direct sequencing. Mutations were detected in the MECP2 gene in approximately 60.5% of patients (26 cases/43 cases). The mutations consisted of 14 different types, including 9 missense mutations, 4 nonsense mutations and 1 frameshift mutation. Of these, three mutations (G161E, T311M, p385fsX409) were newly identified and were determined to be disease-causing mutations by PCR- RFLP and direct sequencing analysis. Most of the mutations were located within MBD (42.3%) and TRD (50%). T158M, R270X, and R306C mutations were identified at a high frequency. Additionally, an intronic SNP (IVS3+23C>G) was newly identified in three of the patients. IVS3+23C>G may be a disease-related and Korea-specific SNP for RTT. L100V and A201V are apparently disease-causing mutations in Korean RTT, contrary to previous studies. Disease-causing mutations and polymorphisms are important tools for diagnosing RTT in Koreans. The experimental procedures used in this study should be considered for clinical molecular biologic diagnosis.
Exp Mol Med 2006 Apr 30
PMID:Diagnostic mutational analysis of MECP2 in Korean patients with Rett syndrome. 1667 65


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