Constitutive activation of mTORC1 signaling induced by biallelic loss-of-function mutations in SZT2 underlies a discernible neurodevelopmental disease

概要

[introduction]
　There have been increasing number of reports of SZT2-relatedneurological diseases, the main symptoms of which are epilepsy, developmental delay,macrocephaly and a dysmorphic corpus callosum. SZT2 functions as a regulator ofmechanistic target of rapamycin complex 1 (mTORC1) signaling in cultured human celllines and mouse tissues. However, it remains to be determined whether mutations inSZT2 in human patients alter mTORC1 signaling. In this study, we aimed to investigatethe functional consequence of biallelic SZT2 variants in Epstein-Barr virus-inducedlymphoblastoid cell lines (LCLs) established from two patients with a typicalSZT2-related neurodevelopmental disease.

[Materials and methods]
　We evaluated two patients with SZT2 variants who havealready been described, and three healthy control subjects. Epstein-Barr virus-inducedLCLs were established from peripheral blood using a standard method.

[Results]
　Increased phosphorylation of S6 kinase and S6 was identified inpatient-derived cell lines under amino acid-starved condition, suggestive of constitutivehyperactivation of mTORC1 signaling. This result was validated by constitutivelysosomal localization of mTOR in patients’ LCLs. Furthermore, patients’ LCLs displayan excessive response to slight amino acid stimulation.

[Discussion]
　Our data suggest the loss-of-function nature of SZT2 mutations in thepatients, and consequent hyperactivation of mTORC1 signaling in response to bothamino acid starvation and stimulation in their LCLs. By these functional analyses, thepathogenicity of newly identified SZT2 variants can be determined, allowing for moredetailed characterization of genotype-phenotype correlations.

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