Language

English

Publication Date

2-6-2025

Journal

American Journal of Human Genetics

DOI

10.1016/j.ajhg.2024.12.019

PMID

39824192

PMCID

PMC11866974

PubMedCentral® Posted Date

1-1-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Nutrient-dependent mTORC1 regulation upon amino acid deprivation is mediated by the KICSTOR complex, comprising SZT2, KPTN, ITFG2, and KICS2, recruiting GATOR1 to lysosomes. Previously, pathogenic SZT2 and KPTN variants have been associated with autosomal recessive intellectual disability and epileptic encephalopathy. We identified bi-allelic KICS2 variants in eleven affected individuals presenting with intellectual disability and epilepsy. These variants partly affected KICS2 stability, compromised KICSTOR complex formation, and demonstrated a deleterious impact on nutrient-dependent mTORC1 regulation of 4EBP1 and S6K. Phosphoproteome analyses extended these findings to show that KICS2 variants changed the mTORC1 proteome, affecting proteins that function in translation, splicing, and ciliogenesis. Depletion of Kics2 in zebrafish resulted in ciliary dysfunction consistent with a role of mTORC1 in cilia biology. These in vitro and in vivo functional studies confirmed the pathogenicity of identified KICS2 variants. Our genetic and experimental data provide evidence that variants in KICS2 are a factor involved in intellectual disability due to its dysfunction impacting mTORC1 regulation and cilia biology.

Keywords

Humans, Intellectual Disability, Mechanistic Target of Rapamycin Complex 1, Epilepsy, Zebrafish, Mutation, Animals, Alleles, Male, Female, Cilia, Child

Published Open-Access

yes

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