RESUMO
Down syndrome (DS) is defined by the presence of a third copy of chromosome 21. Several comorbidities can be found in these patients, such as intellectual disability (ID), muscle weakness, hypotonia, congenital heart disease, and autoimmune diseases. The molecular mechanisms playing a role in the development of such comorbidities are still unclear. The regulation and expression of genes that map to chromosome 21 are dynamic and complex, so it is important to perform global gene expression studies with high statistical power to fully characterize the transcriptome in DS patients. This study was undertaken to evaluate mRNAs and lncRNA expression in patients with DS versus a matched cohort of healthy subjects. RNA sequencing was used to perform this transcriptome study. Differential expression analysis revealed 967 transcripts with padj ≤ 0.05. Among them, 447 transcripts were differentially expressed in patients with DS compared to controls. Particularly, 203 transcripts were down expressed (151 protein-coding mRNAs, 45 lncRNAs, 1 microRNA, 1 mitochondrial tRNA, 1 ribozyme, and 1 small nuclear RNA) and 244 were over expressed (210 protein-coding mRNAs and 34 lncRNAs). Interestingly, deregulated lncRNAs are involved in pathways that play a role in developmental disorders, neurological diseases, DNA replication and repair mechanisms, and cancer development in DS patients. In conclusion, these results suggest a role of lncRNAs in the phenotype of DS patients.
Assuntos
Síndrome de Down/genética , Perfilação da Expressão Gênica/métodos , RNA Longo não Codificante/genética , Transcriptoma/genética , Adulto , Cromossomos Humanos Par 21/genética , Estudos de Coortes , Comorbidade , Reparo do DNA/genética , Replicação do DNA/genética , Deficiências do Desenvolvimento/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/genética , Doenças do Sistema Nervoso/genética , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Sicília , Adulto JovemAssuntos
Síndrome de Down , Mitocôndrias , Células Cultivadas , Fibroblastos , Humanos , RNA MensageiroRESUMO
Typical Xq25 duplications are large and associated with heterogeneous phenotypes. Recently, small duplications involving this genomic region and encompassing the GRIA3 and STAG2 genes have been reported. These Xq25 microduplications are associated with a recognizable syndrome including intellectual disability and distinctive facial appearance. We report on Xq25 microduplications in two unrelated families identified by array comparative genomic hybridization. In both families, the genomic imbalances segregated with the disease in male individuals, while the phenotypes of the heterozygous females appeared to be modulated by their X-inactivation pattern. These rearrangements of about 600 kb involved only three genes: THOC2, XIAP, and STAG2. Further characterization by FISH analyses showed tandem duplication in the Xq25 locus of these genes. These data refine the Xq25 candidate region, identifying a minimal duplicated region of about 270 kb encompassing the XIAP and STAG2 genes. We discuss the function of the genes in the rearrangements and their involvement in the pathogenesis of this disorder.
Assuntos
Antígenos Nucleares/genética , Duplicação Cromossômica , Trissomia/diagnóstico , Trissomia/genética , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genética , Adolescente , Adulto , Idoso , Encéfalo/patologia , Proteínas de Ciclo Celular , Criança , Pré-Escolar , Pontos de Quebra do Cromossomo , Mapeamento Cromossômico , Cromossomos Humanos X/genética , Hibridização Genômica Comparativa , Éxons , Fácies , Feminino , Estudos de Associação Genética , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Aberrações dos Cromossomos Sexuais , Síndrome , Adulto JovemRESUMO
BACKGROUND: The interstitial 6p deletions, involving the 6p22-p24 chromosomal region, are rare events characterized by variable phenotypes and no clear genotype-phenotype correlation has been established so far. RESULTS: High resolution array-CGH identified 1 Mb de novo interstitial deletion in 6p22.3 chromosomal region in a patient affected by severe Intellectual Disability (ID), Autism Spectrum Disorders (ASDs), and electroencephalographic anomalies. This deletion includes ATXN1, DTNBP1, JARID2 and MYLIP genes, known to play an important role in the brain, and the GMPR gene whose function in the nervous system is unknown. CONCLUSIONS: We support the suggestion that ATXN1, DTNBP1, JARID2 and MYLIP are candidate genes for the pathophysiology of ASDs and ID, and we propose that deletion of DTNBP1 and/or JARID2 contributes to the hypotonia phenotype.
