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1.
Mol Psychiatry ; 26(11): 6125-6148, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34188164

RESUMO

While the transcription factor NEUROD2 has recently been associated with epilepsy, its precise role during nervous system development remains unclear. Using a multi-scale approach, we set out to understand how Neurod2 deletion affects the development of the cerebral cortex in mice. In Neurod2 KO embryos, cortical projection neurons over-migrated, thereby altering the final size and position of layers. In juvenile and adults, spine density and turnover were dysregulated in apical but not basal compartments in layer 5 neurons. Patch-clamp recordings in layer 5 neurons of juvenile mice revealed increased intrinsic excitability. Bulk RNA sequencing showed dysregulated expression of many genes associated with neuronal excitability and synaptic function, whose human orthologs were strongly associated with autism spectrum disorders (ASD). At the behavior level, Neurod2 KO mice displayed social interaction deficits, stereotypies, hyperactivity, and occasionally spontaneous seizures. Mice heterozygous for Neurod2 had similar defects, indicating that Neurod2 is haploinsufficient. Finally, specific deletion of Neurod2 in forebrain excitatory neurons recapitulated cellular and behavioral phenotypes found in constitutive KO mice, revealing the region-specific contribution of dysfunctional Neurod2 in symptoms. Informed by these neurobehavioral features in mouse mutants, we identified eleven patients from eight families with a neurodevelopmental disorder including intellectual disability and ASD associated with NEUROD2 pathogenic mutations. Our findings demonstrate crucial roles for Neurod2 in neocortical development, whose alterations can cause neurodevelopmental disorders including intellectual disability and ASD.


Assuntos
Transtorno Autístico , Neuropeptídeos , Animais , Transtorno Autístico/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Córtex Cerebral/metabolismo , Humanos , Camundongos , Neurônios/metabolismo , Neuropeptídeos/metabolismo , Prosencéfalo/metabolismo , Fatores de Transcrição/metabolismo
3.
Patient Educ Couns ; 103(1): 127-135, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31521424

RESUMO

OBJECTIVE: Growing use of clinical exome sequencing (CES) has led to an increased burden of genomic education. Self-guided educational tools can minimize the educational burden for genetic counselors (GCs). The effectiveness of these tools must be evaluated. METHODS: Parents of patients offered CES were randomized to watch educational videos before their visit or to receive routine care. Parents and GCs were surveyed about their experiences following the sessions. The responses of the video (n = 102) and no-video (n = 105) groups were compared. RESULTS: GCs reported no significant differences between parents in the video and no-video groups on genetics knowledge or CES knowledge. In contrast, parents' scores on genetics knowledge questions were lower in the video than no-video group (p = 0.007). Most parents reported the videos were informative, and the groups did not differ in satisfaction with GCs or decisions to have CES. CONCLUSION: GCs and parents perceived the videos to be beneficial. However, lower scores on genetics knowledge questions highlight the need for careful development of educational tools. PRACTICE IMPLICATIONS: Educational tools should be developed and assessed for effectiveness with the input of all stakeholders before widespread implementation. Better measures of the effectiveness of these educational tools are needed.


Assuntos
Conselheiros , Aconselhamento Genético , Exoma , Humanos , Pais , Educação de Pacientes como Assunto
4.
Nat Commun ; 10(1): 4112, 2019 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-31511512

RESUMO

Many neuropsychiatric risk genes contribute to epigenetic regulation but little is known about specific chromatin-associated mechanisms governing the formation of neuronal connectivity. Here we show that transcallosal connectivity is critically dependent on C11orf46, a nuclear protein encoded in the chromosome 11p13 WAGR risk locus. C11orf46 haploinsufficiency was associated with hypoplasia of the corpus callosum. C11orf46 knockdown disrupted transcallosal projections and was rescued by wild type C11orf46 but not the C11orf46R236H mutant associated with intellectual disability. Multiple genes encoding key regulators of axonal development, including Sema6a, were hyperexpressed in C11orf46-knockdown neurons. RNA-guided epigenetic editing of Sema6a gene promoters via a dCas9-SunTag system with C11orf46 binding normalized SEMA6A expression and rescued transcallosal dysconnectivity via repressive chromatin remodeling by the SETDB1 repressor complex. Our study demonstrates that interhemispheric communication is sensitive to locus-specific remodeling of neuronal chromatin, revealing the therapeutic potential for shaping the brain's connectome via gene-targeted designer activators and repressor proteins.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/genética , Corpo Caloso/metabolismo , Epigênese Genética , Edição de Genes , Proteínas Nucleares/metabolismo , Regiões Promotoras Genéticas , Semaforinas/genética , Animais , Axônios/metabolismo , Epigenoma , Regulação da Expressão Gênica , Predisposição Genética para Doença , Células HEK293 , Histona-Lisina N-Metiltransferase , Humanos , Camundongos Endogâmicos C57BL , Rede Nervosa/metabolismo , Neuritos/metabolismo , Fenótipo , Ligação Proteica , Proteínas Metiltransferases/metabolismo
5.
Biol Psychiatry ; 80(10): 765-774, 2016 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-27184921

RESUMO

BACKGROUND: Early childhood malnutrition affects 113 million children worldwide, impacting health and increasing vulnerability for cognitive and behavioral disorders later in life. Molecular signatures after childhood malnutrition, including the potential for intergenerational transmission, remain unexplored. METHODS: We surveyed blood DNA methylomes (~483,000 individual CpG sites) in 168 subjects across two generations, including 50 generation 1 individuals hospitalized during the first year of life for moderate to severe protein-energy malnutrition, then followed up to 48 years in the Barbados Nutrition Study. Attention deficits and cognitive performance were evaluated with the Connors Adult Attention Rating Scale and Wechsler Abbreviated Scale of Intelligence. Expression of nutrition-sensitive genes was explored by quantitative reverse transcriptase polymerase chain reaction in rat prefrontal cortex. RESULTS: We identified 134 nutrition-sensitive, differentially methylated genomic regions, with most (87%) specific for generation 1. Multiple neuropsychiatric risk genes, including COMT, IFNG, MIR200B, SYNGAP1, and VIPR2 showed associations of specific methyl-CpGs with attention and IQ. IFNG expression was decreased in prefrontal cortex of rats showing attention deficits after developmental malnutrition. CONCLUSIONS: Early childhood malnutrition entails long-lasting epigenetic signatures associated with liability for attention and cognition, and limited potential for intergenerational transmission.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/etiologia , Comportamento Animal , Disfunção Cognitiva/etiologia , Metilação de DNA , Epigênese Genética , Córtex Pré-Frontal/metabolismo , Desnutrição Proteico-Calórica/complicações , Adolescente , Adulto , Animais , Transtorno do Deficit de Atenção com Hiperatividade/genética , Barbados , Disfunção Cognitiva/genética , Metilação de DNA/genética , Modelos Animais de Doenças , Epigênese Genética/genética , Seguimentos , Humanos , Lactente , Pessoa de Meia-Idade , Inquéritos Nutricionais , Desnutrição Proteico-Calórica/genética , Ratos , Adulto Jovem
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