Dataset Information

Autism gene variant causes hyperserotonemia, serotonin receptor hypersensitivity, social impairment and repetitive behavior.

ABSTRACT: Fifty years ago, increased whole-blood serotonin levels, or hyperserotonemia, first linked disrupted 5-HT homeostasis to Autism Spectrum Disorders (ASDs). The 5-HT transporter (SERT) gene (SLC6A4) has been associated with whole blood 5-HT levels and ASD susceptibility. Previously, we identified multiple gain-of-function SERT coding variants in children with ASD. Here we establish that transgenic mice expressing the most common of these variants, SERT Ala56, exhibit elevated, p38 MAPK-dependent transporter phosphorylation, enhanced 5-HT clearance rates and hyperserotonemia. These effects are accompanied by altered basal firing of raphe 5-HT neurons, as well as 5HT(1A) and 5HT(2A) receptor hypersensitivity. Strikingly, SERT Ala56 mice display alterations in social function, communication, and repetitive behavior. Our efforts provide strong support for the hypothesis that altered 5-HT homeostasis can impact risk for ASD traits and provide a model with construct and face validity that can support further analysis of ASD mechanisms and potentially novel treatments.

SUBMITTER: Veenstra-VanderWeele J

PROVIDER: S-EPMC3325657 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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Autism gene variant causes hyperserotonemia, serotonin receptor hypersensitivity, social impairment and repetitive behavior.

Veenstra-VanderWeele Jeremy J Muller Christopher L CL Iwamoto Hideki H Sauer Jennifer E JE Owens W Anthony WA Shah Charisma R CR Cohen Jordan J Mannangatti Padmanabhan P Jessen Tammy T Thompson Brent J BJ Ye Ran R Kerr Travis M TM Carneiro Ana M AM Crawley Jacqueline N JN Sanders-Bush Elaine E McMahon Douglas G DG Ramamoorthy Sammanda S Daws Lynette C LC Sutcliffe James S JS Blakely Randy D RD

Proceedings of the National Academy of Sciences of the United States of America 20120319 14

Fifty years ago, increased whole-blood serotonin levels, or hyperserotonemia, first linked disrupted 5-HT homeostasis to Autism Spectrum Disorders (ASDs). The 5-HT transporter (SERT) gene (SLC6A4) has been associated with whole blood 5-HT levels and ASD susceptibility. Previously, we identified multiple gain-of-function SERT coding variants in children with ASD. Here we establish that transgenic mice expressing the most common of these variants, SERT Ala56, exhibit elevated, p38 MAPK-dependent t ...[more]

PMID: 22431635

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Project description:Eighty-seven percent of a large sample of children with autism spectrum disorder (ASD) are at risk for motor impairment (Bhat, Physical Therapy, 2020, 100, 633-644). In spite of the high prevalence for motor impairment in children with ASD, it is not considered among the diagnostic criteria or specifiers within DSM-V. In this article, we analyzed the SPARK study dataset (n = 13,887) to examine associations between risk for motor impairment using the Developmental Coordination Disorder-Questionnaire (DCD-Q), social communication impairment using the Social Communication Questionnaire (SCQ), repetitive behavior severity using the Repetitive Behaviors Scale - Revised (RBS-R), and parent-reported categories of cognitive, functional, and language impairments. Upon including children with ASD with cognitive impairments, 88.2% of the SPARK sample was at risk for motor impairment. The relative risk ratio for motor impairment in children with ASD was 22.2 times greater compared to the general population and that risk further increased up to 6.2 with increasing social communication (5.7), functional (6.2), cognitive (3.8), and language (1.6) impairments as well as repetitive behavior severity (5.0). Additionally, the magnitude of risk for motor impairment (fine- and gross-motor) increased with increasing severity of all impairment types with medium to large effects. These findings highlight the multisystem nature of ASD, the need to recognize motor impairments as one of the diagnostic criteria or specifiers for ASD, and the need for appropriate motor screening and assessment of children with ASD. Interventions must address not only the social communication and cognitive/behavioral challenges of children with ASD but also their motor function and participation. LAY ABSTRACT: Eighty-eight percent of the SPARK sample of children with ASD were at risk for motor impairment. The relative risk for motor impairment was 22.2 times greater in children with ASD compared to the general population and the risk increased with more social communication, repetitive behavior, cognitive, and functional impairment. It is important to recognize motor impairments as one of the diagnostic criteria or specifiers for ASD and there is a need to administer appropriate motor screening, assessment, and interventions in children with ASD.

Project description:BackgroundRASopathies are genetic syndromes that result from pathogenic variants in the RAS-MAPK cellular signaling pathway. These syndromes, which include neurofibromatosis type 1, Noonan syndrome, cardiofaciocutaneous syndrome, and Costello syndrome, are associated with a complex array of medical and behavioral health complications. Despite a heightened risk for social challenges and autism spectrum disorder (ASD), few studies have compared different aspects of social behavior across these conditions. It is also unknown whether the underlying neuropsychological characteristics that contribute to social competence and socially empathetic ("prosocial") behaviors differ in children with RASopathies as compared to children with nonsyndromic (i.e., idiopathic) ASD.MethodsIn this cross-sectional, survey-based investigation, caregivers of preschool and school-aged children with RASopathies (n = 202) or with idiopathic ASD (n = 109) provided demographic, medical, and developmental information about their child, including psychiatric comorbidities. For children who were able to communicate verbally, caregivers also completed standardized rating scales to assess social competence and empathetic behavior as well as symptoms of hyperactivity/inattention and emotional problems.ResultsAs compared to children with idiopathic ASD, children with RASopathies were rated as demonstrating more resilience in the domain of empathy relative to their overall social competence. Similarities and differences emerged in the psychological factors that predicted social behavior in these two groups. Stronger communication skills and fewer hyperactive-impulsive behaviors were associated with increased empathy and social competence for both groups. Greater emotional challenges were associated with lower social competence for children with RASopathies and stronger empathy for children with idiopathic ASD. Among children with RASopathy and a co-occurring ASD diagnosis, socially empathetic behaviors were observed more often as compared to children with idiopathic ASD.ConclusionsFindings suggest that the development of social behavior among children with RASopathies involves a distinct pattern of strengths and weaknesses as compared to a behaviorally defined disorder (idiopathic ASD). Identification of areas of resilience as well as behavioral and social challenges will support more targeted intervention.

Dataset Information

Autism gene variant causes hyperserotonemia, serotonin receptor hypersensitivity, social impairment and repetitive behavior.

Publications

Autism gene variant causes hyperserotonemia, serotonin receptor hypersensitivity, social impairment and repetitive behavior.

Similar Datasets

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