Mutacje w genie KLHL15 związane z ogniskową epilepsją i zaburzeniami neurorozwojowymi

PURPOSE: KLHL15 encodes Kelch-like protein 15, an adapter for the Cullin3 (CUL3) E3 ubiquitin ligase complex. CUL3 variants are linked to developmental disorders and epilepsy. However, the association between KLHL15 variants and epilepsy is unclear. This study aimed to explore the association of KLHL15 with epilepsy. METHODS: Exome sequencing was performed in patients with non-acquired focal epilepsy. Pathogenic variants' effects were assessed via protein modeling. Single-cell analysis of KLHL15 expression was performed to explore neurodevelopmental mechanisms. Its interacting proteins were analyzed via network diffusion analysis to explore functional links with epilepsy and neurodevelopmental disorders (NDDs). RESULTS: KLHL15 missense variants were identified in four unrelated focal epilepsy cases with NDDs. These variants, absent in gnomAD, were predicted to alter protein stability. The observed genotype-phenotype associations suggest that variants within the domain may be implicated in epilepsy and neurodevelopmental disorders. Spatiotemporal analysis showed KLHL15 was highly expressed in the developing brain. Single-cell sequencing of organoids and adult brain demonstrated predominant expression in excitatory neurons across developmental stages. Functional enrichment revealed KLHL15 as a central component of the ubiquitin-proteasome pathway and Cullin-based E3 complexes. Network diffusion analysis confirmed functional links to epilepsy with NDDs genes. CONCLUSION: KLHL15 variants are correlated with focal epilepsy with NDDs. The observed domain variants contribute to elucidating genotype-phenotype relationships. The spatiotemporal expression profiles and functional network provide crucial insights into the pathogenic mechanisms of KLHL15 variants.