Anti-TSC2 monoclonal antibody, clone FQ2173Z

Background:Knowledge is increasing about TSC-Associated Neuropsychiatric Disorders (TAND), but little is known about the potentially confounding effects of intellectual ability (IA) on the rates of TAND across age, sex, and genotype. We evaluated TAND in (a) children vs. adults, (b) males vs. females, and (c)TSC1vs.TSC2mutations, after stratification for levels of IA, in a large, international cohort. Methods:Individuals of any age with a documented visit for TSC in the 12 months prior to enrolment were included. Frequency and percentages of baseline TAND manifestations were presented by categories of IA (no intellectual disability [ID, intelligence quotient (IQ)>70]; mild ID [IQ 50-70]; moderate-to-profound ID [IQ<50]). Chi-square tests were used to test associations between ID and TAND manifestations. The association between TAND and age (children vs. adults), sex (male vs. female), and genotype (TSC1vs.TSC2) stratified by IA levels were examined using the Cochran-Mantel-Haenszel tests. Results:Eight hundred and ninety four of the 2,211 participants had formal IQ assessments. There was a significant association (P< 0.05) between levels of IA and the majority of TAND manifestations, except impulsivity (P= 0.12), overactivity (P= 0.26), mood swings (P= 0.08), hallucinations (P= 0.20), psychosis (P= 0.06), depressive disorder (P= 0.23), and anxiety disorder (P= 0.65). Once controlled for IA, children had higher rates of overactivity, but most behavioral difficulties were higher in adults. At the psychiatric level, attention deficit hyperactivity disorder (ADHD) was seen at higher rates in children while anxiety and depressive disorders were observed at higher rates in adults. Compared to females, males showed significantly higher rates of impulsivity and overactivity, as well as autism spectrum disorder (ASD) and ADHD. No significant age or sex differences were observed for academic difficulties or neuropsychological deficits. After controlling for IA no genotype-TAND associations were observed, except for higher rates of self-injury in individuals withTSC2mutations. Conclusions:Findings suggest IA as risk marker for most TAND manifestations. We provide the first evidence of male preponderance of ASD and ADHD in individuals with TSC. The study also confirms the association betweenTSC2and IA but, once controlling for IA, disproves the previously reportedTSC2association with ASD and with most other TAND manifestations.

In Schizosaccharomyces pombe, a general strategy for survival in response to environmental changes is sexual differentiation, which is triggered by TORC1 inactivation. However, mechanisms of TORC1 regulation in fission yeast remain poorly understood. In this study, we found that Pef1, which is an ortholog of mammalian CDK5, regulates the initiation of sexual differentiation through positive regulation of TORC1 activity. Conversely, deletion of pef1 leads to activation of autophagy and subsequent excessive TORC1 reactivation during the early phases of the nitrogen starvation response. This excessive TORC1 reactivation results in the silencing of the Ste11-Mei2 pathway and mating defects. Additionally, we found that pef1 genetically interacts with tsc1 and tsc2 for TORC1 regulation, and physically interacts with three cyclins, Clg1, Pas1 and Psl1. The double deletion of clg1 and pas1 promotes activation of autophagy and TORC1 during nitrogen starvation, similar to what is seen in pef1 Delta cells. Overall, our work suggests that Pef1-Clg1 and Pef1-Pas1 complexes regulate initiation of sexual differentiation through control of the TSC-TORC1 pathway and autophagy.