RESUMEN
Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition with a strong genetic basis. We accurately assessed 209 ASD subjects, categorized in complex (47) and essential (162), and performed array comparative genomic hybridization to identify pathogenic and recurrent Copy Number Variants (CNVs). We found 117 CNVs in 75 patients, 11 classified as pathogenic. The complex ASD subjects have higher frequency of pathogenic CNVs with a diagnostic yield of 12.8%. Familiality, cognitive and verbal abilities, severity of autistic symptoms, neuroimaging and neurophysiological findings are not related to genetic data. This study identifies loci of interest for ASD and highlights the importance of a careful phenotypic characterization, as complex ASD is related to higher rate of pathogenic CNVs.
Asunto(s)
Trastorno del Espectro Autista , Trastornos Generalizados del Desarrollo Infantil , Humanos , Niño , Trastorno del Espectro Autista/diagnóstico , Trastorno del Espectro Autista/genética , Hibridación Genómica Comparativa/métodos , Variaciones en el Número de Copia de ADN/genética , CogniciónRESUMEN
The authors wish to make the corrections to this paper [...].
RESUMEN
The presence of redundant copy number variants (CNVs) in groups of patients with neurological diseases suggests that these variants could have pathogenic effect. We have collected array comparative genomic hybridization (CGH) data of about 2,500 patients affected by neurocognitive disorders and we observed that CNVs in 2p16.3 locus were as frequent as those in 15q11.2, being both the most frequent unbalances in our cohort of patients. Focusing to 2p16.3 region, unbalances involving NRXN1 coding region have been already associated with neuropsychiatric disorders, although with incomplete penetrance, but little is known about CNVs located proximal to the gene, in the long noncoding RNA AK127244. We found that, in our cohort of patients with neuropsychiatric disorders, the frequency of CNVs involving AK127244 was comparable to that of NRXN1 gene. Patients carrying 2p16.3 unbalances shared some common clinical characteristics regardless NRXN1 and AK127244 CNVs localization, suggesting that the AK127244 long noncoding RNA could be involved in neurocognitive disease with the same effect of NRXN1 unbalances. AK127244 as well as NRXN1 unbalances seem to have a particular influence on language development, behavior or mood, according with the topographic correlation between NRXN1 expression and prefrontal cortex functions.
Asunto(s)
Cromosomas Humanos Par 2 , Trastornos Mentales/genética , ARN Largo no Codificante/genética , ARN no Traducido/genética , Adolescente , Adulto , Proteínas de Unión al Calcio , Estudios de Casos y Controles , Moléculas de Adhesión Celular Neuronal/genética , Niño , Preescolar , Estudios de Cohortes , Hibridación Genómica Comparativa/métodos , Variaciones en el Número de Copia de ADN , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Trastornos Mentales/metabolismo , Persona de Mediana Edad , Proteínas del Tejido Nervioso/genética , Moléculas de Adhesión de Célula Nerviosa , Fenotipo , ARN Largo no Codificante/metabolismo , ARN no Traducido/metabolismoRESUMEN
We investigated in vitro the properties of selected populations of cancer stem-like cells defined as tumorospheres that were obtained from human glioblastoma. We also assessed their potential and capability of differentiating into mature cells of the central nervous system. In vivo, their tumorigenicity was confirmed after transplantation into the brain of non-obese diabetic/severe combined immunodeficient (NOD-SCID) mice. The angiogenic potential of tumorospheres and glioblastoma-derived cells grown as adherent cells was revealed by evaluating the release of angiogenic factors such as vascular endothelial growth factor and CXCL12 by ELISA, as well as by rat aortic ring assay. The proliferative response of tumorospheres in the presence of CXCL12 was observed for the first time. Multidrug resistance-associated proteins 1 and 3 as well as other molecules conferring multidrug resistance were higher when compared with primary adherent cells derived from the same tumor. Finally, we obtained cells from the tumor developing after grafting that clearly expressed the putative neural stem cell marker CD133 as shown by FACS analysis and also nestin and CXCR4. The cells' positivity for glial fibrillary acidic protein was very low. Moreover these cells preserved their angiogenic potential. We conclude that human glioblastoma could contain tumor cell subsets with angiogenic and chemoresistance properties and that this chemoresistance potential is highly preserved by immature cells whereas the angiogenic potential is, to a higher extent, a property of mature cells. A better understanding of the features of these cell subsets may favor the development of more specifically targeted therapies.