RESUMO
Therapeutic concentrations of lithium salts inhibit glycogen synthase kinase 3 beta (GSK3ß) and phosphoinositide (PI) signaling suggesting that abnormal activation of these pathways could be a factor in the pathophysiology of bipolar disorder (BD). Involvement of these pathways is also supported by recent genome-wide association studies (GWASs). One way investigators have investigated the molecular basis of BD and the therapeutic action of lithium is by microarray expression studies, since both GSK3ß- and PI-mediated signal transduction pathways are coupled to transcriptional activation and inhibition. However, expression profiling has some limitations and investigators cannot use the approach to analyze fetal brain tissue, arguably the most relevant biological structure related to the development of genetically based psychiatric disorders. To address these shortcomings, the authors have taken a novel approach using chromatin immunoprecipitation-enriched material annealed to microarrays (ChIP-chip) targeting genes in fetal brain tissue bound by ß-catenin, a transcription factor that is directly regulated by GSK3ß. The promoters for 640 genes were found to be bound by ß-catenin, many of which are known schizophrenia (SZ), autism spectrum disorder (ASD), and BD candidates, including CACNA1B, NRNG, SNAP29, FGFR1, PCDH9, and nine others identified in recently published GWASs and genome-wide searches for copy number variants (CNVs). The findings suggest that seemingly disparate candidate genes for SZ and BD can be incorporated into a common molecular network revolving around GSK3ß/ß-catenin signaling. In addition, the finding that a putative lithium-responsive pathway may influence a subgroup of SZ and ASD candidate genes could have therapeutic implications.
Assuntos
Transtorno Bipolar/genética , Imunoprecipitação da Cromatina/métodos , Redes Reguladoras de Genes , Regiões Promotoras Genéticas , Esquizofrenia/genética , beta Catenina/genética , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/metabolismo , Encéfalo , Caderinas/genética , Canais de Cálcio Tipo N/genética , Criança , Transtornos Globais do Desenvolvimento Infantil/genética , Feminino , Feto , Estudo de Associação Genômica Ampla , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Humanos , Fosfatos de Inositol/antagonistas & inibidores , Fosfatos de Inositol/metabolismo , Lítio/metabolismo , Lítio/farmacologia , Análise de Sequência com Séries de Oligonucleotídeos , Protocaderinas , Proteínas Qb-SNARE/genética , Proteínas Qc-SNARE/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Esquizofrenia/tratamento farmacológico , Esquizofrenia/mortalidade , Transdução de Sinais/genética , Ativação Transcricional , beta Catenina/metabolismoRESUMO
Copy number variants (CNVs) affecting the neurexin 1 (NRXN1) gene have been found in a subgroup of patients with schizophrenia (SZ). NRXN1 expression is complex, with multiple alternative splice forms generated from two major transcripts; NRXN1alpha and NRXN1beta. The majority of CNVs in SZ are deletions affecting the proximal NRXN1alpha exons and promoter region. Rare chromosomal events are useful in understanding the genetic basis of complex psychiatric disorders since affected genes become feasible targets to analyze for more subtle genetic alterations. As a first step towards this goal, we resequenced the NRXN1alpha promoter region in 170 patients with SZ and a similar number of controls. Two rare mutations were identified in the patient population. One previously unknown single nucleotide polymorphism (SNP) was found in controls. Bioinformatics analysis suggests that binding to several transcription factors may be affected by the minor alleles. The findings suggest that in addition to chromosomal alterations disrupting the NRXN1alpha promoter, rare point mutations in the region may also be involved in SZ pathogenesis.
