Bi-allelic KICS2 mutations impair KICSTOR complex-mediated mTORC1 regulation, causing intellectual disability and
Rebecca Buchert1, Martin D Burkhalter2, Chrisovalantou Huridou3
1Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
American Journal of Human Genetics
|January 17, 2025
Summary
Genetic variants in KICS2 cause intellectual disability and epilepsy by disrupting mTORC1 signaling and cilia function. This study identifies KICS2 as a key gene involved in neurodevelopmental disorders.
Area of Science:
- Cellular Biology
- Genetics
- Neuroscience
Background:
- The KICSTOR complex, including KICS2, regulates nutrient-dependent mTORC1 signaling.
- Pathogenic variants in SZT2 and KPTN are linked to intellectual disability and epilepsy.
- The role of KICS2 in these disorders was previously unknown.
Purpose of the Study:
- To investigate the role of KICS2 variants in intellectual disability and epilepsy.
- To elucidate the functional impact of KICS2 variants on mTORC1 signaling and cellular processes.
Main Methods:
- Genetic analysis of affected individuals with bi-allelic KICS2 variants.
- In vitro studies assessing KICS2 stability, KICSTOR complex formation, and mTORC1 pathway activity.
- Phosphoproteome analysis to identify downstream effects of KICS2 variants.
- In vivo studies using zebrafish models to assess ciliary function.
Main Results:
- Bi-allelic KICS2 variants were identified in eleven individuals with intellectual disability and epilepsy.
- These variants impaired KICS2 stability, KICSTOR complex formation, and mTORC1 regulation.
- KICS2 variants altered the mTORC1 proteome, affecting translation, splicing, and ciliogenesis.
- Kics2 depletion in zebrafish caused ciliary dysfunction, linking mTORC1 to cilia biology.
Conclusions:
- KICS2 variants are pathogenic and cause intellectual disability and epilepsy.
- Dysfunctional KICS2 disrupts mTORC1 signaling and impacts cilia biology, contributing to neurodevelopmental disorders.
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