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1.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(9): 968-971, 2020 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-32820509

RESUMO

OBJECTIVE: To detect potential variants of MECP2 gene in three pedigrees affected with Rett syndrome (RTT). METHODS: All exons and their flanking regions of the MECP2 gene were subjected to Sanger sequencing and multiplex ligation-dependent probe amplification assay. RESULTS: The probands of pedigrees 1 and 2 have respectively carried a c.965C>G and a c.1157_1197del41 variant of the MECP2 gene, while the proband of pedigree 3 carried a heterozygous deletional variant in exon 4 of the MECP2 gene. CONCLUSION: Variants of the MECP2 gene probably underlay the RTT in the three pedigrees. Above finding has enriched the spectrum of MECP2 gene variants, and provided a guidance for the patients upon preimplantation genetic testing and prenatal diagnosis.


Assuntos
Proteína 2 de Ligação a Metil-CpG , Síndrome de Rett , Éxons , Feminino , Testes Genéticos , Humanos , Proteína 2 de Ligação a Metil-CpG/genética , Mutação , Linhagem , Gravidez , Síndrome de Rett/genética
2.
Lancet Neurol ; 19(8): 689-698, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32702338

RESUMO

The X-linked gene encoding MECP2 is involved in two severe and complex neurodevelopmental disorders. Loss of function of the MeCP2 protein underlies Rett syndrome, whereas duplications of the MECP2 locus cause MECP2 duplication syndrome. Research on the mechanisms by which MeCP2 exerts effects on gene expression in neurons, studies of animal models bearing different disease-causing mutations, and more in-depth observations of clinical presentations have clarified some issues even as they have raised further questions. Yet there is enough evidence so far to suggest possible approaches to therapy for these two diseases that could go beyond attempting to address specific signs and symptoms (of which there are many) and instead target the pathophysiology underlying MECP2 disorders. Further work could bring antisense oligonucleotides, deep brain stimulation, and gene therapy into the clinic within the next decade or so.


Assuntos
Retardo Mental Ligado ao Cromossomo X/genética , Retardo Mental Ligado ao Cromossomo X/terapia , Proteína 2 de Ligação a Metil-CpG/genética , Mutação/genética , Síndrome de Rett/genética , Síndrome de Rett/terapia , Humanos
4.
Sci Data ; 7(1): 178, 2020 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-32546682

RESUMO

A vast amount of public RNA-sequencing datasets have been generated and used widely to study transcriptome mechanisms. These data offer precious opportunity for advancing biological research in transcriptome studies such as alternative splicing. We report the first large-scale integrated analysis of RNA-Seq data of splicing factors for systematically identifying key factors in diseases and biological processes. We analyzed 1,321 RNA-Seq libraries of various mouse tissues and cell lines, comprising more than 6.6 TB sequences from 75 independent studies that experimentally manipulated 56 splicing factors. Using these data, RNA splicing signatures and gene expression signatures were computed, and signature comparison analysis identified a list of key splicing factors in Rett syndrome and cold-induced thermogenesis. We show that cold-induced RNA-binding proteins rescue the neurite outgrowth defects in Rett syndrome using neuronal morphology analysis, and we also reveal that SRSF1 and PTBP1 are required for energy expenditure in adipocytes using metabolic flux analysis. Our study provides an integrated analysis for identifying key factors in diseases and biological processes and highlights the importance of public data resources for identifying hypotheses for experimental testing.


Assuntos
Fatores de Processamento de RNA , RNA-Seq , Adipócitos/metabolismo , Processamento Alternativo , Animais , Linhagem Celular , Temperatura Baixa , Conjuntos de Dados como Assunto , Ribonucleoproteínas Nucleares Heterogêneas/genética , Camundongos , Proteína de Ligação a Regiões Ricas em Polipirimidinas/genética , Síndrome de Rett/genética , Fatores de Processamento de Serina-Arginina/genética , Termogênese/genética , Transcriptoma
6.
Mol Cell ; 79(1): 84-98.e9, 2020 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-32526163

RESUMO

Rett syndrome (RTT), mainly caused by mutations in methyl-CpG binding protein 2 (MeCP2), is one of the most prevalent intellectual disorders without effective therapies. Here, we used 2D and 3D human brain cultures to investigate MeCP2 function. We found that MeCP2 mutations cause severe abnormalities in human interneurons (INs). Surprisingly, treatment with a BET inhibitor, JQ1, rescued the molecular and functional phenotypes of MeCP2 mutant INs. We uncovered that abnormal increases in chromatin binding of BRD4 and enhancer-promoter interactions underlie the abnormal transcription in MeCP2 mutant INs, which were recovered to normal levels by JQ1. We revealed cell-type-specific transcriptome impairment in MeCP2 mutant region-specific human brain organoids that were rescued by JQ1. Finally, JQ1 ameliorated RTT-like phenotypes in mice. These data demonstrate that BRD4 dysregulation is a critical driver for RTT etiology and suggest that targeting BRD4 could be a potential therapeutic opportunity for RTT.


Assuntos
Azepinas/farmacologia , Encéfalo/patologia , Proteínas de Ciclo Celular/metabolismo , Interneurônios/patologia , Proteína 2 de Ligação a Metil-CpG/fisiologia , Síndrome de Rett/patologia , Fatores de Transcrição/metabolismo , Transcriptoma/efeitos dos fármacos , Triazóis/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Proteínas de Ciclo Celular/genética , Feminino , Células-Tronco Embrionárias Humanas/efeitos dos fármacos , Células-Tronco Embrionárias Humanas/metabolismo , Células-Tronco Embrionárias Humanas/patologia , Humanos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/patologia , Interneurônios/efeitos dos fármacos , Interneurônios/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação , Fenótipo , Síndrome de Rett/tratamento farmacológico , Síndrome de Rett/genética , Síndrome de Rett/metabolismo , Fatores de Transcrição/genética
7.
BMC Med Genet ; 21(1): 99, 2020 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-32393352

RESUMO

BACKGROUND: To date, at least 746 genes have been identified to cause intellectual disability (ID). Among them, mutations in the Methyl CpG binding protein 2 (MECP2) gene are the leading cause of Rett syndrome and associated ID. METHODS: Considering the large number of ID-associated genes, we applied trio-based whole-exome sequencing (trio-WES) and in silico analysis for genetic diagnosis of 294 children with ID. RESULTS: Three de novo heterozygous mutations [NM_004992.3: c.502C > T, p.(Arg168*), c.916C > T, p.(Arg306Cys), and c.879C > G, p.(Ile293Met)] in MECP2 were identified in three unrelated girls. The first two mutations were detected in two patients who were diagnosed as typical Rett syndrome, X-linked ID and psychomotor retardation. The third mutation (c.879C > G), a previously unreported, was found in a 6-year-old girl with ID, microcephaly, severe underweight and psychomotor retardation. Particularly, this extremely rare de novo mutation (DNM) is located in the transcriptional repression domain (TRD) of MECP2, where at least 62 different causal mutations are identified. CONCLUSIONS: We identified three DNMs in MECP2 in a cohort of 294 individuals with ID. The novel c.879C > G mutation, as a likely pathogenic allele, may become a risk factor associated with X-linked ID, microcephaly and psychomotor retardation.


Assuntos
Predisposição Genética para Doença , Deficiência Intelectual/genética , Proteína 2 de Ligação a Metil-CpG/genética , Síndrome de Rett/genética , Criança , Pré-Escolar , Feminino , Heterozigoto , Humanos , Deficiência Intelectual/patologia , Microcefalia/genética , Microcefalia/patologia , Mutação , Linhagem , Fenótipo , Síndrome de Rett/patologia , Sequenciamento Completo do Exoma
8.
Gene ; 743: 144612, 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32222533

RESUMO

Structural Maintenance of Chromosomes (SMCs) are part of a large family of ring complexes that participates in a number of DNA transactions. Among SMCs, SMC1A gene is unique. It encodes a subunit of the cohesin-core complex that tethers sister chromatids together to ensure correct chromosome segregation in both mitosis and meiosis. As a member of the cohesin ring, SMC1A takes part in gene transcription regulation and genome organization; and it participates in the DNA Damage Repair (DDR) pathway, being phosphorylated by Ataxia Telangiectasia Mutated (ATM) and Ataxia Telangiectasia and Rad3 Related (ATR) threonine/serine kinases. It is also a component of the Recombination protein complex (RC-1) involved in DNA repair by recombination. SMC1A pathogenic variants have been described in Cornelia de Lange syndrome (CdLS), a human rare disease, and recently SMC1A variants have been associated with epilepsy or resembling Rett syndrome phenotype. Finally, SMC1A variants have been identified in several human cancers. In this review, our current knowledge of the SMC1A gene has been summarized.


Assuntos
Proteínas de Ciclo Celular/genética , Proteínas Cromossômicas não Histona/genética , Segregação de Cromossomos , Instabilidade Genômica , Reparo de DNA por Recombinação , Animais , Proteínas de Ciclo Celular/metabolismo , Proteínas Cromossômicas não Histona/metabolismo , Síndrome de Cornélia de Lange/genética , Modelos Animais de Doenças , Epilepsia/genética , Humanos , Meiose/genética , Camundongos , Mitose/genética , Mutação , Neoplasias/genética , Síndrome de Rett/genética
9.
Biochim Biophys Acta Mol Basis Dis ; 1866(6): 165730, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32070770

RESUMO

Widespread random monoallelic gene expression (RMAE) effects influence about 10% of human genes. However, the mechanisms by which RME of autosomal genes is established and those by which it is maintained both remain open questions. Because the choice of allelic expression is randomly performed cell-by-cell, the RMAE mechanism is not observable in non-clonal cell populations or in whole tissues. Several target genes of MeCP2, the gene involved in Rett syndrome (RTT), have been previously described as subject to RMAE, suggesting that MeCP2 may be involved in the establishment and/or maintenance of RME of autosomal genes. To improve our knowledge on this largely unknown phenomenon, and to study the role of MeCP2 in RMAE, we compared RMA gene expression profiles in clonal cell cultures expressing wild-type MeCP2 versus mutant MeCP2 from a RTT patient carrying a pathogenic non-sense variant. Our data clearly demonstrated that MeCP2 deficiency does not affect significantly allelic gene expression of X-linked genes, imprinted genes as well as the RMAE profile in the majority of genes. However, the functional deficiency in MeCP2 appeared to disrupt the mono-allelic or the bi-allelic expression of at least 49 genes allowing us to define a specific signature of MECP2 mutated clones.


Assuntos
Proteína 2 de Ligação a Metil-CpG/genética , Síndrome de Rett/genética , Alelos , Desequilíbrio Alélico/genética , Regulação da Expressão Gênica/genética , Genes Ligados ao Cromossomo X/genética , Humanos , Mutação/genética , Fenótipo , Síndrome de Rett/patologia
10.
BMC Med Genet ; 21(1): 21, 2020 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-32005172

RESUMO

BACKGROUND: More than 95% of individuals with RTT have mutations in methyl-CpG-binding protein 2 (MECP2), whose protein product modulates gene transcription. The disorder is caused by mutations in a single gene and the disease severity in affected individuals can be quite variable. Specific MECP2 mutations may lead phenotypic variability and different degrees of disease severity. It is known that low bone mass is a frequent and early complication of subjects with Rett syndrome. As a consequence of the low bone mass Rett girls are at an increased risk of fragility fractures. This study aimed to investigate if specific MECP2 mutations may affects the degree of involvement of the bone status in Rett subjects. METHODS: In 232 women with Rett syndrome (mean age 13.8 ± 8.3 yrs) we measured bone mineral density at whole body and at femur (BMD-FN and BMD-TH) by using a DXA machine (Hologic QDR 4500). QUS parameters were assessed at phalanxes by Bone Profiler-IGEA (amplitude dependent speed of sound: AD-SoS and bone transmission time: BTT). Moreover, ambulation capacity (independent or assisted), fracture history and presence of scoliosis were assessed. We divided the subjects with the most common point mutations in two group based on genotype-phenotype severity; in particular, there has been consensus in recognising that the mutations R106T, R168X, R255X, R270X are considered more severe. RESULTS: As aspect, BMD-WB, BMD-FN and BMD-TH were lower in subjects with Rett syndrome that present the most severe mutations with respect to subjects with Rett syndrome with less severe mutations, but the difference was statistically significant only for BMD-FN and BMD-TH (p < 0.05). Also both AD-SoS and BTT values were lower in subjects that present the most severe mutations with respect to less severe mutations but the difference was not statistically significant. Moreover, subjects with Rett syndrome with more severe mutations present a higher prevalence of scoliosis (p < 0.05) and of inability to walk (p < 0.05). CONCLUSION: This study confirms that MECP2 mutation type is a strong predictor of disease severity in subjects with Rett syndrome. In particular, the subjects with more severe mutation present a greater deterioration of bone status, and a higher prevalence of scoliosis and inability to walk.


Assuntos
Doenças Ósseas/genética , Proteína 2 de Ligação a Metil-CpG/genética , Osteoporose/genética , Síndrome de Rett/genética , Adolescente , Adulto , Densidade Óssea/genética , Doenças Ósseas/diagnóstico por imagem , Doenças Ósseas/fisiopatologia , Criança , Pré-Escolar , Feminino , Fraturas Ósseas/diagnóstico por imagem , Fraturas Ósseas/genética , Fraturas Ósseas/fisiopatologia , Humanos , Masculino , Mutação , Osteoporose/diagnóstico por imagem , Osteoporose/fisiopatologia , Síndrome de Rett/diagnóstico por imagem , Síndrome de Rett/fisiopatologia , Escoliose/diagnóstico por imagem , Escoliose/genética , Escoliose/fisiopatologia , Índice de Gravidade de Doença , Adulto Jovem
11.
Sci Rep ; 10(1): 2491, 2020 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-32051524

RESUMO

Dendritic atrophy, defined as the reduction in complexity of the neuronal arborization, is a hallmark of several neurodevelopmental disorders, including Rett Syndrome (RTT). RTT, affecting 1:10,000 girls worldwide, is mainly caused by mutations in the MECP2 gene and has no cure. We describe here an in vitro model of dendritic atrophy in Mecp2-/y mouse hippocampal primary cultures, suitable for phenotypic drug-screening. Using High-Content Imaging techniques, we systematically investigated the impact of culturing determinants on several parameters such as neuronal survival, total dendritic length, dendritic endpoints, soma size, cell clusterization, spontaneous activity. Determinants included cell-seeding density, glass or polystyrene substrates, coating with poly-Ornithine with/without Matrigel and miniaturization from 24 to 96-half surface multiwell plates. We show that in all plate-sizes at densities below 320 cells/mm2, morphological parameters remained constant while spontaneous network activity decreased according to the cell-density. Mecp2-/y neurons cultured at 160 cells/mm2 density in 96 multiwell plates, displayed significant dendritic atrophy and showed a marked increase in dendritic length following treatment with Brain-derived neurotrophic factor (BDNF) or Mirtazapine. In conclusion, we have established a phenotypic assay suitable for fast screening of hundreds of compounds, which may be extended to other neurodevelopmental diseases with dendritic atrophy.


Assuntos
Dendritos/patologia , Avaliação Pré-Clínica de Medicamentos/métodos , Fármacos Neuroprotetores/farmacologia , Fenótipo , Síndrome de Rett/genética , Animais , Fator Neurotrófico Derivado do Encéfalo/farmacologia , Células Cultivadas , Dendritos/efeitos dos fármacos , Hipocampo/citologia , Proteína 2 de Ligação a Metil-CpG/genética , Camundongos , Camundongos Endogâmicos C57BL , Mirtazapina/farmacologia , Síndrome de Rett/patologia
12.
Sci Rep ; 10(1): 1074, 2020 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-31974426

RESUMO

The methyl-CpG-binding protein 2 gene, MECP2, is an X chromosome-linked gene encoding the MeCP2 protein, and mutations of MECP2 cause Rett syndrome (RTT). Previous study has shown that re-expression of SUMO-modified MeCP2 in Mecp2-null neurons rescues synaptic and behavioral deficits in Mecp2 conditional knockout mice, whereas about 12-fold decrease in Wnt6 mRNA level was found in MeCP2K412R sumo-mutant mice. Here, we examined the role of Wnt6 in MeCP2 T158A mouse model of RTT. Results show that lentiviral delivery of Wnt6 to the amygdala ameliorates locomotor impairment and social behavioral deficits in these animals. MeCP2 T158A mice show decreased level of GSK-3ß phosphorylation and increased level of ß-catenin phosphorylation. They also show reduced level of MeCP2 SUMOylation. These alterations were also restored by lenti-Wnt6 transduction. Further, both BDNF and IGF-1 expressions are decreased in MeCP2 T158A mice. Overexpression of Wnt6 increases Bdnf and Igf-1 promoter activity in HEK293T cells in a dose-dependent manner. Lenti-Wnt6 transduction to the amygdala similarly increases the mRNA level and protein expression of BDNF and IGF-1 in MeCP2 T158A mice. Moreover, environmental enrichment (EE) similarly ameliorates the locomotor and social behavioral deficits in MeCP2 T158A mice. One of the mechanisms underlying EE is mediated through enhanced MeCP2 SUMOylation and increased Wnt6 expression in these animals by EE.


Assuntos
Proteína 2 de Ligação a Metil-CpG/genética , Proteína 2 de Ligação a Metil-CpG/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Síndrome de Rett/metabolismo , Proteínas Wnt/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Modelos Animais de Doenças , Glicogênio Sintase Quinase 3 beta/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Knockout , Mutação de Sentido Incorreto , Proteínas Proto-Oncogênicas/genética , Síndrome de Rett/genética , Transdução de Sinais , Proteínas Wnt/genética
14.
Hum Genet ; 139(4): 499-512, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31980904

RESUMO

CHD8, which encodes Chromodomain helicase DNA-binding protein 8, is one of a few well-established Autism Spectrum Disorder (ASD) genes. Over 60 mutations have been reported in subjects with variable phenotypes, but little is known concerning genotype-phenotype correlations. We have identified four novel de novo mutations in Chinese subjects: two nonsense variants (c.3562C>T/p.Arg1188X, c.2065C>A/p.Glu689X), a splice site variant (c.4818-1G>A) and a missense variant (c.3502T>A/p.Tyr1168Asn). Three of these were identified from a 445-member ASD cohort by ASD gene panel sequencing of the 96 subjects who remained negative after molecular testing for copy number variation, Rett syndrome, FragileX and tuberous sclerosis complex (TSC). The fourth (p.Glu689X) was detected separately by diagnostic trio exome sequencing. We used diagnostic instruments and a comprehensive review of phenotypes, including prenatal and postnatal growth parameters, developmental milestones, and dysmorphic features to compare these four subjects. In addition to autism, they also presented with prenatal onset macrocephaly, intellectual disability, overgrowth during puberty, sleep disorder, and dysmorphic features, including broad forehead with prominent supraorbital ridges, flat nasal bridge, telecanthus and large ears. For further comparison, we compiled a comprehensive list of CHD8 variants from the literature and databases, which revealed constitutive and somatic truncating variants in the HELIC (Helicase-C) domain in ASD and in cancer patients, respectively, but not in the general population. Furthermore, HELIC domain mutations were associated with a severe phenotype defined by a greater number of clinical features, lower verbal IQ, and a prominent, consistent pattern of overgrowth as measured by weight, height and head circumference. Overall, this study adds to the ASD-associated loss-of-function mutations in CHD8 and highlights the clinical importance of the HELIC domain of CHD8.


Assuntos
Transtorno do Espectro Autista/genética , Códon sem Sentido , Proteínas de Ligação a DNA/genética , Síndrome do Cromossomo X Frágil/genética , Transtornos do Desenvolvimento da Linguagem/genética , Mutação de Sentido Incorreto , Fenótipo , Síndrome de Rett/genética , Fatores de Transcrição/genética , Esclerose Tuberosa/genética , Transtorno do Espectro Autista/enzimologia , Criança , Feminino , Síndrome do Cromossomo X Frágil/enzimologia , Humanos , Transtornos do Desenvolvimento da Linguagem/enzimologia , Masculino , Domínios Proteicos , Síndrome de Rett/enzimologia , Esclerose Tuberosa/enzimologia
15.
Gene ; 732: 144337, 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-31958484

RESUMO

Rett syndrome (RTT) is an X-linked severe neurological disorder. Mutations in Methyl-CpG-Binding Protein2 (MECP2) gene are the main cause of RTT disease. In this study, we report the results of screening the MECP2 gene for mutations in 7 Iranian patients with RTT syndrome. MECP2 sequencing identified two novel mutations in the heterozygous state, a splice mutation, c.354G>T, p.Gly119Gly, resulting in a premature splice-donor site and a 20-bp deletion, c.1167-1186del20 (p.P390Rfs), leading to modifying the c-terminal parts of the protein and it also changes the reading frames of all coding sequence downstream of the mutation. Multiple sequence alignment showed that amino acid changes occurred in the well conserved protein regions across species. Based on the results of this study and literature reviews, about 70% of mutations are found in exon 3 and 4 of the MECP2 gene, and mutations in exon 4 are more common than other exons. Therefore, it is recommended that exon 4 to be a priority for screening the genetic analysis of RTT patients.


Assuntos
Proteína 2 de Ligação a Metil-CpG/genética , Mutação , Síndrome de Rett/genética , Sequência de Aminoácidos , Criança , Éxons , Feminino , Genótipo , Humanos , Irã (Geográfico) , Masculino , Proteína 2 de Ligação a Metil-CpG/química , Fenótipo , Homologia de Sequência de Aminoácidos
16.
J Neurosci ; 40(7): 1514-1526, 2020 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-31911459

RESUMO

The neurodevelopmental disorder Rett syndrome is caused by mutations in the gene Mecp2 Misexpression of the protein MECP2 is thought to contribute to neuropathology by causing dysregulation of plasticity. Female heterozygous Mecp2 mutants (Mecp2het ) failed to acquire a learned maternal retrieval behavior when exposed to pups, an effect linked to disruption of parvalbumin-expressing inhibitory interneurons (PV) in the auditory cortex. Nevertheless, how dysregulated PV networks affect the neural activity dynamics that underlie auditory cortical plasticity during early maternal experience is unknown. Here we show that maternal experience in WT adult female mice (WT) triggers suppression of PV auditory responses. We also observe concomitant disinhibition of auditory responses in deep-layer pyramidal neurons that is selective for behaviorally relevant pup vocalizations. These neurons further exhibit sharpened tuning for pup vocalizations following maternal experience. All of these neuronal changes are abolished in Mecp2het , suggesting that they are an essential component of maternal learning. This is further supported by our finding that genetic manipulation of GABAergic networks that restores accurate retrieval behavior in Mecp2het also restores maternal experience-dependent plasticity of PV. Our data are consistent with a growing body of evidence that cortical networks are particularly vulnerable to mutations of Mecp2 in PV neurons. Moreover, our work links, for the first time, impaired in vivo cortical plasticity in awake Mecp2 mutant animals to a natural, ethologically relevant behavior.SIGNIFICANCE STATEMENT Rett syndrome is a genetic disorder that includes language communication problems. Nearly all Rett syndrome is caused by mutations in the gene that produces the protein MECP2, which is important for changes in brain connectivity believed to underlie learning. We previously showed that female Mecp2 mutants fail to learn a simple maternal care behavior performed in response to their pups' distress cries. This impairment appeared to critically involve inhibitory neurons in the auditory cortex called parvalbumin neurons. Here we record from these neurons before and after maternal experience, and we show that they adapt their response to pup calls during maternal learning in nonmutants, but not in mutants. This adaptation is partially restored by a manipulation that improves learning.


Assuntos
Córtex Auditivo/fisiopatologia , Deficiências da Aprendizagem/fisiopatologia , Comportamento Materno/fisiologia , Proteína 2 de Ligação a Metil-CpG/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Plasticidade Neuronal/fisiologia , Estimulação Acústica , Animais , Animais Recém-Nascidos , Animais Lactentes , Córtex Auditivo/patologia , Feminino , Neurônios GABAérgicos/fisiologia , Glutamato Descarboxilase/deficiência , Glutamato Descarboxilase/fisiologia , Interneurônios/fisiologia , Deficiências da Aprendizagem/genética , Proteína 2 de Ligação a Metil-CpG/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Proteínas do Tecido Nervoso/deficiência , Técnicas de Patch-Clamp , Células Piramidais/fisiologia , Síndrome de Rett/genética , Análise de Célula Única , Vocalização Animal
17.
Mol Cell ; 77(2): 294-309.e9, 2020 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-31784358

RESUMO

Mutations in the methyl-DNA-binding repressor protein MeCP2 cause the devastating neurodevelopmental disorder Rett syndrome. It has been challenging to understand how MeCP2 regulates transcription because MeCP2 binds broadly across the genome and MeCP2 mutations are associated with widespread small-magnitude changes in neuronal gene expression. We demonstrate here that MeCP2 represses nascent RNA transcription of highly methylated long genes in the brain through its interaction with the NCoR co-repressor complex. By measuring the rates of transcriptional initiation and elongation directly in the brain, we find that MeCP2 has no measurable effect on transcriptional elongation, but instead represses the rate at which Pol II initiates transcription of highly methylated long genes. These findings suggest a new model of MeCP2 function in which MeCP2 binds broadly across highly methylated regions of DNA, but acts at transcription start sites to attenuate transcriptional initiation.


Assuntos
Metilação de DNA/genética , Proteína 2 de Ligação a Metil-CpG/genética , Proteínas Repressoras/genética , Transcrição Genética/genética , Animais , Encéfalo/fisiologia , DNA/genética , Masculino , Camundongos , Camundongos Knockout , Mutação/genética , Neurônios/fisiologia , RNA/genética , Síndrome de Rett/genética
18.
J Autism Dev Disord ; 50(1): 118-126, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31535341

RESUMO

Rett syndrome (RTT) is a rare monogenic disorder affecting 1 in 10,000 live female births causing severe neurodegenerative symptoms. We analyzed the molecular genetic variants in the gene encoding the methyl-CpG binding protein 2 (MECP2) of 16 girls with RTT. Their mutation profile was as follows; Already described variants: p.R168X in 25% (n = 4), p.T158M in 25% (n = 4), p.R255X in 12.5% (n = 2), p.R133C in 12.5% (n = 2), p.R294X in 6.25% (n = 1), p.K177X in 6.25% (n = 1). Novel variants: a large deletion (c.868_1188del321) in 6.25% (n = 1) and a p.X499L in 6.25% (n = 1). We also looked at the genotype to phenotype correlation of these variants. Most of the mutations were C>T in CpG hot spot as seen in other populations.


Assuntos
Proteína 2 de Ligação a Metil-CpG/genética , Síndrome de Rett/genética , Adulto , Feminino , Genótipo , Humanos , Mutação , Fenótipo , Doenças Raras , Síndrome de Rett/etnologia , Sri Lanka
19.
Orv Hetil ; 160(51): 2036-2039, 2019 Dec.
Artigo em Húngaro | MEDLINE | ID: mdl-31838863

RESUMO

Here we report on a severe, neonatal onset epileptic encephalopathy manifested in a currently 2-year-old boy with no family history of neurological disease. Extensive clinical investigations were unable to clarify the etiology of the infant's condition characterized by drug-resistant seizures and markedly delayed developmental skills. As in this class of disorders a genetic cause might be identified, a next-generation sequencing (NGS) epilepsy panel examination consisting of 128 genes was initiated for a correct diagnosis. The genetic analysis identified a previously undescribed hemizygous missense mutation in the MECP2 gene. Similarly to other, X-linked dominant disorders, Rett syndrome was originally hypothesized to be lethal in males. This theory, however, has been revised. The aim of this report is to review the wide spectrum of neurodevelopmental diseases observed in male patients carrying mutations in the MECP2 gene classically associated with Rett syndrome in girls. To the author's knowledge, this is the first report in Hungary to document MECP2 mutation of a male patient diagnosed by molecular genetic testing. Orv Hetil. 2019; 160(51): 2036-2039.


Assuntos
Retardo Mental Ligado ao Cromossomo X/genética , Proteína 2 de Ligação a Metil-CpG/genética , Mutação/genética , Síndrome de Rett/genética , Pré-Escolar , Humanos , Hungria , Masculino , Retardo Mental Ligado ao Cromossomo X/diagnóstico , Retardo Mental Ligado ao Cromossomo X/fisiopatologia , Biologia Molecular , Fenótipo , Síndrome de Rett/fisiopatologia
20.
Elife ; 82019 12 23.
Artigo em Inglês | MEDLINE | ID: mdl-31868585

RESUMO

Methyl-CpG-binding-Protein 2 (MeCP2) is an abundant nuclear protein highly enriched in neurons. Here we report live-cell single-molecule imaging studies of the kinetic features of mouse MeCP2 at high spatial-temporal resolution. MeCP2 displays dynamic features that are distinct from both highly mobile transcription factors and immobile histones. Stable binding of MeCP2 in living neurons requires its methyl-binding domain and is sensitive to DNA modification levels. Diffusion of unbound MeCP2 is strongly constrained by weak, transient interactions mediated primarily by its AT-hook domains, and varies with the level of chromatin compaction and cell type. These findings extend previous studies of the role of the MeCP2 MBD in high affinity DNA binding to living neurons, and identify a new role for its AT-hooks domains as critical determinants of its kinetic behavior. They suggest that limited nuclear diffusion of MeCP2 in live neurons contributes to its local impact on chromatin structure and gene expression.


Assuntos
Cromatina/metabolismo , Proteína 2 de Ligação a Metil-CpG/metabolismo , Neurônios/metabolismo , Proteínas Nucleares/metabolismo , Animais , Sequência de Bases , Sítios de Ligação , Núcleo Celular/metabolismo , Cerebelo/citologia , Cerebelo/metabolismo , DNA/metabolismo , Metilação de DNA , Proteínas de Ligação a DNA/metabolismo , Feminino , Dosagem de Genes , Regulação da Expressão Gênica no Desenvolvimento , Histonas/metabolismo , Cinética , Masculino , Proteína 2 de Ligação a Metil-CpG/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Animais , Neurônios/citologia , Ligação Proteica , Síndrome de Rett/genética , Fatores de Transcrição/metabolismo
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