RESUMO
BACKGROUND: MicroRNAs (miRNAs) are non-coding gene transcripts involved in post-transcriptional regulation of genes. Recent studies identified miRNAs as important regulators of learning and memory in model organisms. So far, no mutations in specific miRNA genes have been associated with impaired cognitive functions. METHODS AND RESULTS: In three sibs and two unrelated patients with intellectual disability (ID), overlapping 1p21.3 deletions were detected by genome-wide array analysis. The shortest region of overlap included dihydropyrimidine dehydrogenase (DPYD) and microRNA 137 (MIR137). DPYD is involved in autosomal recessive dihydropyrimidine dehydrogenase deficiency. Hemizygous DPYD deletions were previously suggested to contribute to a phenotype with autism spectrum disorder and speech delay. Interestingly, the mature microRNA transcript microRNA-137 (miR-137) was recently shown to be involved in modulating neurogenesis in adult murine neuronal stem cells. Therefore, this study investigated the possible involvement of MIR137 in the 1p21.3-deletion phenotype. The patients displayed a significantly decreased expression of both precursor and mature miR-137 levels, as well as significantly increased expression of the validated downstream targets microphthalmia-associated transcription factor (MITF) and Enhancer of Zeste, Drosophila, Homologue 2 (EZH2), and the newly identified target Kruppel-like factor 4 (KLF4). The study also demonstrated significant enrichment of miR-137 at the synapses of cortical and hippocampal neurons, suggesting a role of miR-137 in regulating local synaptic protein synthesis machinery. CONCLUSIONS: This study showed that dosage effects of MIR137 are associated with 1p21.3 microdeletions and may therefore contribute to the ID phenotype in patients with deletions harbouring this miRNA. A local effect at the synapse might be responsible.
Assuntos
Deleção Cromossômica , Deficiência Intelectual/genética , MicroRNAs/genética , Adolescente , Adulto , Animais , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 1/metabolismo , Variações do Número de Cópias de DNA , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Di-Hidrouracila Desidrogenase (NADP)/genética , Di-Hidrouracila Desidrogenase (NADP)/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste , Feminino , Dosagem de Genes , Regulação da Expressão Gênica , Hipocampo/citologia , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Deficiência Intelectual/metabolismo , Deficiência Intelectual/patologia , Fator 4 Semelhante a Kruppel , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Masculino , MicroRNAs/metabolismo , Fator de Transcrição Associado à Microftalmia/genética , Fator de Transcrição Associado à Microftalmia/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Neurônios/patologia , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Complexo Repressor Polycomb 2 , Polimorfismo de Nucleotídeo Único , Cultura Primária de Células , Ratos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , TransfecçãoRESUMO
Deletions of the distal 3q22.3 region encompassing the gene forkhead transcription factor FOXL2 (FOXL2) usually result in intellectual disability (ID) and the highly recognizable blepharophimosis-ptosis-epicanthus inversus syndrome (BPES). We encountered three patients with molecularly defined interstitial deletions distal to the FOXL2 gene. They present with remarkably similar manifestations comprising variable ID, a coarse facial appearance, including prominent nose and eyebrows, hypogonadism and skin pigmentation abnormalities, and they share an approximately 8.8 Mb overlapping 3q24q25 deletion. Interestingly, one of the present patients was described previously in a clinical report with emphasis on her clinical similarity to the Wisconsin syndrome, suggesting that Wisconsin syndrome might be caused by a (micro) deletion within the 3q24q25 region.