Abstract
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. Here, we assess the relevance of these signalopathies in ASD reviewing genetic, human cell model, rodent studies and clinical trials. 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. Taken together, 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.
Highlights
Inactivating mutations of RHEB or MTOR result in Autism Spectrum Disorder (ASD), developmental abnormalities or epilepsy resulting from mTOR hyperactivity, their frequency is low [33,34,35]
In a more recent study by Satterstrom et al [19] de novo protein truncating and missense variants were reported as likely disease causing: i.e., in the 6430 ascertained ASDindividuals, mutations of RAS-associated genes were most frequently identified in SYNGAP1 (ASD 14, intellectual disability (ID) 17) or Neurofibromatosis type 1 (NF1) (ASD 4, ID 3)
IPSC lines are a valuable resource for neurodevelopmental disease research, so far most of the cell lines generated for the various genes associated with Noonan syndrome have only been studied in the context of the Noonan-associated cardiomyopathy (RAF1 [162,163], leucine zipper–like transcriptional regulator 1 (LZTR1) [164], MRAS [165]) and juvenile myelomonocytic leukemia (PTPN11 [166])
Summary
Disruption of discrete signaling cascades often presents with specific phenotypic profiles or syndromes. To this end, the most prominent groups of syndromes associated with ASD are related to disruptions of the. MTOR (mechanistic Target of Rapamycin, mTORopathies) and the RAS-RAF-MEK-ERK pathway (RASopathies). The association of these specific signalopathies with core features of ASD is well founded and based on observations made in patients, animal, and cellular models. We review the current knowledge on the syndromes associated with a disruption of the mTOR and RAS-RAF-MEK-ERK pathways and assess the potential impact of these signalopathies with the aim to evaluate their relevance in the clinical setting
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