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Hum Mol Genet ; 23(10): 2752-68, 2014 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-24381304

RESUMEN

Rare copy number variants (CNVs) disrupting ASTN2 or both ASTN2 and TRIM32 have been reported at 9q33.1 by genome-wide studies in a few individuals with neurodevelopmental disorders (NDDs). The vertebrate-specific astrotactins, ASTN2 and its paralog ASTN1, have key roles in glial-guided neuronal migration during brain development. To determine the prevalence of astrotactin mutations and delineate their associated phenotypic spectrum, we screened ASTN2/TRIM32 and ASTN1 (1q25.2) for exonic CNVs in clinical microarray data from 89 985 individuals across 10 sites, including 64 114 NDD subjects. In this clinical dataset, we identified 46 deletions and 12 duplications affecting ASTN2. Deletions of ASTN1 were much rarer. Deletions near the 3' terminus of ASTN2, which would disrupt all transcript isoforms (a subset of these deletions also included TRIM32), were significantly enriched in the NDD subjects (P = 0.002) compared with 44 085 population-based controls. Frequent phenotypes observed in individuals with such deletions include autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), speech delay, anxiety and obsessive compulsive disorder (OCD). The 3'-terminal ASTN2 deletions were significantly enriched compared with controls in males with NDDs, but not in females. Upon quantifying ASTN2 human brain RNA, we observed shorter isoforms expressed from an alternative transcription start site of recent evolutionary origin near the 3' end. Spatiotemporal expression profiling in the human brain revealed consistently high ASTN1 expression while ASTN2 expression peaked in the early embryonic neocortex and postnatal cerebellar cortex. Our findings shed new light on the role of the astrotactins in psychopathology and their interplay in human neurodevelopment.


Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad/genética , Trastornos Generalizados del Desarrollo Infantil/genética , Glicoproteínas/genética , Proteínas del Tejido Nervioso/genética , Factores de Transcripción/genética , Adolescente , Adulto , Estudios de Casos y Controles , Niño , Preescolar , Cromosomas Humanos Par 9 , Variaciones en el Número de Copia de ADN , Exones , Femenino , Expresión Génica , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Glicoproteínas/metabolismo , Humanos , Lactante , Recién Nacido , Masculino , Proteínas del Tejido Nervioso/metabolismo , Especificidad de Órganos , Fenotipo , Polimorfismo de Nucleótido Simple , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/metabolismo , Factores de Riesgo , Eliminación de Secuencia , Factores de Transcripción/metabolismo , Sitio de Iniciación de la Transcripción , Proteínas de Motivos Tripartitos , Ubiquitina-Proteína Ligasas , Adulto Joven
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