New Molecular Insights in Schizophrenia: ConstitutionalMicroduplications or Microdeletions (CNVs) Spanning NeuralGenes and a miRNA Dysregulation in Distinct Regions of theBrain Linked to the Disease

摘要

Recent use of microarrays uncovered two novel abnormalities in schizophrenic individuals: constitutional copy number variants(CNVs) and a dysregulation of miRNAs in the brain. Key neural genes were the most consistently implicated in microdeletions,microduplications and disruptions caused by CNVs that resulted in gene-dosage defects. The most common abnormalities were recurrent“de novo” microdeletions at 1q21.1, 15q11.2 and 15q13.3 which were considered risk factors in a minority of patients. The microdeletionsof 22q11.2 were confirmed as a risk factor for schizophrenia (SZ). In addition other more rare “de novo” CNVs mostly found in singlecases seem to predispose to the disease. The miRNA dysregulation in regions of the brain thought to be related to SZ (dorsal prefrontalcortex and superior temporal gyrus) may trigger downstream a faulty gene expression. CNVs and dysregulated miRNAs probably impairbrain development, the differentiation and function of neurons, and the synaptic neurotransmission through deficiencies on specificgenes and pathways. The overall findings herald an enhanced understanding of SZ and reveal a complex network of genes and regulatorymechanisms related to the pathophysiology and heterogeneous genetic etiology. The defective genes and miRNAs that were identifiedmight become therapeutic targets of clinical relevance and useful parameters to monitor and classify patients more accurately.