Relevance to Autism

A previously observed gain-of-function missense variant in the MTOR gene (c.5395G>A; p.Glu1799Lys) that likely arose through gonadal mosaicism was identified in two affected brothers, aged 6 and 23 years, who presented with ASD, intellectual disability, macrocephaly (+5 SD), and megalencephaly (Mroske et al., 2015). Sequencing of patients with focal cortical dysplasia, hemimegalencephaly, and diffuse megalencephaly in Mirzaa et al., 2016 identified the p.Glu1799Lys missense variant as a constitutional de novo variant in identical twin brothers with autism at 17 years of age, seizures, and diffuse megalencephaly; functional analysis of this variant in electroporated rat neurons demonstrated constitutive activation following starvation (as measured by S6 immunofluoroscence) and increased neuronal cell size.. Mutations in the MTOR gene are also associated with Smith-Kingsmore syndrome (SKS, OMIM 616638), a syndromic from of intellectual disability characterized by macrocephaly, seizures, umbilical hernia, and facial dysmorphic features (Lee et al., 2012; Baynam et al., 2015). Mosaic MTOR variants have also been identified in patients presenting with focal cortical dysplasia and megalencephaly (Mirzaa et al., 2016). Gordo et al., 2018 identified 4 new cases of Smith-Kingsmore syndrome, reviewed the phenotypic profiles of 23 patients previously described in the literature, and reported that autistic spectrum disorder was a clinical finding in 8/27 SKS cases (29.6%). Poole et al., 2021 characterized 16 individuals from 12 unrelated families with the MTOR c.5395G>A p.(Glu1799Lys) variant; all 16 individuals presented with intellectual disability and megalencephaly, and behavioral problems were described in 14/16 patients (88%), with autism spectrum disorder/autistic traits being the most frequently observed (10 patients).

Molecular Function

The protein encoded by this gene belongs to a family of phosphatidylinositol kinase-related kinases. These kinases mediate cellular responses to stresses such as DNA damage and nutrient deprivation. This kinase is a component of two distinct complexes, mTORC1, which controls protein synthesis, cell growth and proliferation, and mTORC2, which is a regulator of the actin cytoskeleton, and promotes cell survival and cell cycle progression. This protein acts as the target for the cell-cycle arrest and immunosuppressive effects of the FKBP12-rapamycin complex. Inhibitors of mTOR are used in organ transplants as immunosuppressants, and are being evaluated for their therapeutic potential in SARS-CoV-2 infections. Mutations in this gene are associated with Smith-Kingsmore syndrome and somatic focal cortical dysplasia type II.

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Model Summary

Absence of mTOR in Drd1-expressing striatal medial spiny neurons in male mice results in decreased activity of downstream targets of mTORC1, decreased spontaneous locomotion, impaired social interaction, and decreased marble-burying behavior, a Kv1.1-induced increase in the fast phase of afterhyperpolarization and decreased distal spine density in striatal direct pathway striatal projection neurons, with no changes in anxiety. Treatment with RhoA and inactivation of voltage-gated potassium channels 1.1 (Kv1.1)rescued some phenotypes.

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