The EU funded Project launched October 26th in Paris. The Moleclar Genetics Laboratory of CAPPP at the Franfkurt University is joining forces with 26 other world-leading research groups to inmprove our understanding the risk and resilience factors for mental well-being.
We are thrilled to announce our new collaboration with Neurolentech GmbH to generate patient-specific cellular models for neurodevelopmental disorders such as Autism Spectrum Disorder (ASD). Our common aim is to investigate disease mechanisms at the cellular, functional and molecular levels with the goal to generate tools and data to foster therapeutic drug development.
The EU funded Project launched October 26th in Paris. The Moleclar Genetics Laboratory of CAPPP at the Franfkurt University is joining forces with 26 other world-leading research groups to inmprove our understanding the risk and resilience factors for mental well-being.
We are thrilled to announce our new collaboration with Neurolentech GmbH to generate patient-specific cellular models for neurodevelopmental disorders such as Autism Spectrum Disorder (ASD). Our common aim is to investigate disease mechanisms at the cellular, functional and molecular levels with the goal to generate tools and data to foster therapeutic drug development.
Conduct Disorder (CD) is an impairing psychiatric disorder of childhood and adolescence characterized by aggressive and dissocial behavior. Environmental factors such as maternal smoking during pregnancy, socio-economic status, trauma, or early life stress are associated with CD. We performed a genome-wide methylation sequencing of 49 CD girls and 50 matched typically developing controls. We identified a 12% increased methylation 5’ of the neurite modulator SLITRK5 (FDR = 0.0046) in cases within a glucocorticoid receptor binding site. Functionally, methylation positively correlated with gene expression in lymphoblastoid cell lines. In addition, we found the epigenetic signatures of a gene network activated in the thalamus during early childhood correlated with the effect of parental education on CD status possibly mediating its protective effect.
Conduct Disorder (CD) is observed in children and adolescents. Kids with CD are much more aggressive and antisocial as typical children would be. Several factors in the child’s environment can increase the risk for such behaviour, for example smoking of the mother during pregnancy, growing up in poverty, or having stressful childhood. In this study, we analyzed the DNA of 49 girls with CD and of 50 girls with age-typical behvaiour. We observed that on one gene, SLITRK5, the methylation of the DNA is increased. This reduced the amount of SLITRK5 in the CD girls. The gene regulates how neurons make branches in the brain. We also found that the pattern of the methylation of the DNA is related to the education of the parents. Here, a higher education of the parents reduced the risk for CD. We think this happens because the DNA-methylation is changed.
Mutations affecting mTOR or RAS signaling underlie defined syndromes (the so-called mTORopathies and RASopathies) with high risk for Autism Spectrum Disorder (ASD). These syndromes show a broad variety of somatic phenotypes including cancers, skin abnormalities, heart disease and facial dysmorphisms. Less well studied are the neuropsychiatric symptoms such as ASD. We conclude that signalopathies have an increased liability for ASD and that, in particular, ASD individuals with dysmorphic features and intellectual disability (ID) have a higher chance for disruptive mutations in RAS- and mTOR-related genes. Studies on rodent and human cell models confirm aberrant neuronal development as the underlying pathology. Human studies further suggest that multiple hits are necessary to induce the respective phenotypes. Recent clinical trials do only report improvements for comorbid conditions such as epilepsy or cancer but not for behavioral aspects. Animal models show that treatment during early development can rescue behavioral phenotypes. We suggest investigating the differential roles of mTOR and RAS signaling in both human and rodent models, and to test drug treatment both during and after neuronal development in the available model systems.
Altered neuronal development is discussed as the underlying pathogenic mechanism of autism spectrum disorders (ASD). Copy number variations of 16p11.2 have recurrently been identified in individuals with ASD. Of the 29 genes within this region, quinolinate phosphoribosyltransferase (QPRT) showed the strongest regulation during neuronal differentiation of SH-SY5Y neuroblastoma cells. The reduction of QPRT altered neuronal morphology of differentiated SH-SY5Y cells. Chemical inhibition as well as complete KO of the gene were lethal upon induction of neuronal differentiation, but not proliferation. Differentially regulated genes were enriched for ASD candidates, and co-regulated gene networks were implicated in the development of the dorsolateral prefrontal cortex, the hippocampus, and the amygdala. Thus, our data suggest that QPRT may play an important role in the pathogenesis of ASD in Chr16p11.2 deletion carriers.
Postal Adress:
AG Chiocchetti
Translational Child Psychiatry
University Hospital Frankfurt
Building 25A, 5th floor
Theodor-Stern-Kai 7
60596 Frankfurt am Main