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 JovenRESUMEN
BACKGROUND: Transport workers generally face a higher-than-average risk of HIV as well as other health challenges. In order to improve understanding of health issues in the maritime sector, including but not limited to HIV/AIDS, and to prepare appropriate responses the International Transport Workers' Federation (ITF) conducted a study of the views and needs of those affiliates. MATERIALS AND METHODS: The ITF carried out two surveys. The first consisted of a questionnaire sent to all ITF seafarer affiliates to establish their concerns about health issues, including the impact of HIV/AIDS, and to assess the extent and nature of existing trade union programmes. The second consisted of a knowledge, attitude and behaviour survey on health, wellbeing and AIDS among a cross-section of individual members administered through anonymous and confidential questionnaires by maritime affiliates in four countries in different regions and an identical online questionnaire through Survey Monkey. RESULTS: For the first survey, replies were received from 35 unions in 30 countries, including major seafarer supplying countries - India, Indonesia, Myanmar, Philippines, Turkey, Ukraine - and major beneficial ownership countries such as Germany, Italy, Norway, and South Korea. Health issues of concern included HIV and other sexually transmitted infections for over three-quarters of them, and then alcohol use, weight control, and mental health. All said they would welcome ITF support in starting or strengthening a programme on general health and/or HIV. Replies were received to the second survey from 615 individual seafarers. Half to three-quarters said they worried about their weight, lack of exercise and drinking; over half felt depressed sometimes or often. There were serious knowledge gaps in a number of areas, especially HIV transmission and prevention, as well as high levels of stigma towards workmates with HIV. CONCLUSIONS: A number of health issues and information gaps remain unaddressed on board and pre-departure. Mental health is especially neglected but the needs emerge clearly. Seafarers believe that companies should provide programmes but also look to their unions for health information and services. The ITF has an important role to play in supporting affiliated unions in developing activities and in providing technical and strategic guidance.