RESUMEN
BACKGROUND: Childhood disintegrative disorder (CDD) is a rare form of autism spectrum disorder (ASD) of unknown etiology. It is characterized by late-onset regression leading to significant intellectual disability (ID) and severe autism. Although there are phenotypic differences between CDD and other forms of ASD, it is unclear if there are neurobiological differences. METHODS: We pursued a multidisciplinary study of CDD (n = 17) and three comparison groups: low-functioning ASD (n = 12), high-functioning ASD (n = 50), and typically developing (n = 26) individuals. We performed whole-exome sequencing (WES), copy number variant (CNV), and gene expression analyses of CDD and, on subsets of each cohort, non-sedated functional magnetic resonance imaging (fMRI) while viewing socioemotional (faces) and non-socioemotional (houses) stimuli and eye tracking while viewing emotional faces. RESULTS: We observed potential differences between CDD and other forms of ASD. WES and CNV analyses identified one or more rare de novo, homozygous, and/or hemizygous (mother-to-son transmission on chrX) variants for most probands that were not shared by unaffected sibling controls. There were no clearly deleterious variants or highly recurrent candidate genes. Candidate genes that were found to be most conserved at variant position and most intolerant of variation, such as TRRAP, ZNF236, and KIAA2018, play a role or may be involved in transcription. Using the human BrainSpan transcriptome dataset, CDD candidate genes were found to be more highly expressed in non-neocortical regions than neocortical regions. This expression profile was similar to that of an independent cohort of ASD probands with regression. The non-neocortical regions overlapped with those identified by fMRI as abnormally hyperactive in response to viewing faces, such as the thalamus, cerebellum, caudate, and hippocampus. Eye-tracking analysis showed that, among individuals with ASD, subjects with CDD focused on eyes the most when shown pictures of faces. CONCLUSIONS: Given that cohort sizes were limited by the rarity of CDD, and the challenges of conducting non-sedated fMRI and eye tracking in subjects with ASD and significant ID, this is an exploratory study designed to investigate the neurobiological features of CDD. In addition to reporting the first multimodal analysis of CDD, a combination of fMRI and eye-tracking analyses are being presented for the first time for low-functioning individuals with ASD. Our results suggest differences between CDD and other forms of ASD on the neurobiological as well as clinical level.
Asunto(s)
Trastorno del Espectro Autista/genética , Encéfalo/fisiopatología , Cromosomas Humanos X/química , Discapacidad Intelectual/genética , Transcriptoma , Proteínas Adaptadoras Transductoras de Señales/genética , Trastorno del Espectro Autista/diagnóstico por imagen , Trastorno del Espectro Autista/fisiopatología , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Mapeo Encefálico , Estudios de Casos y Controles , Niño , Preescolar , Variaciones en el Número de Copia de ADN , Progresión de la Enfermedad , Femenino , Expresión Génica , Humanos , Discapacidad Intelectual/diagnóstico por imagen , Discapacidad Intelectual/fisiopatología , Imagen por Resonancia Magnética , Masculino , Herencia Materna , Proteínas Nucleares/genética , Fenotipo , Polimorfismo Genético , Índice de Severidad de la Enfermedad , Hermanos , Factores de Transcripción/genética , Secuenciación del ExomaRESUMEN
Previous studies from our laboratory have shown that the activation of G(2)-M checkpoint after exposure of MCF-7 breast cancer cells to gamma-irradiation (IR) is dependent on the activation of extracellular signal-regulated kinase 1/2 (ERK1/2) signaling. Studies presented in this report indicate that IR exposure of MCF-7 cells is associated with a marked increase in expression of breast cancer 1 (BRCA1) tumor suppressor, an effect that requires ERK1/2 activation and involves posttranscriptional control mechanisms. Furthermore, reciprocal coimmunoprecipitation, as well as colocalization studies, indicate an interaction between BRCA1 and ERK1/2 in both nonirradiated and irradiated cells. Studies using short hairpin RNA targeting BRCA1 show that BRCA1 expression is necessary for IR-induced G(2)-M cell cycle arrest, as well as ERK1/2 activation in MCF-7 cells. Although BRCA1 expression is not required for IR-induced phosphorylation of ataxia telangiectasia mutated (ATM)-Ser1981, it is required for ATM-mediated downstream signaling events, including IR-induced phosphorylation of Chk2-Thr68 and p53-Ser20. Moreover, BRCA1 expression is also required for IR-induced ATM and rad3 related activation and Chk1 phosphorylation in MCF-7 cells. These results implicate an important interaction between BRCA1 and ERK1/2 in the regulation of cellular response after IR-induced DNA damage in MCF-7 cells.