TBCK Deficiency Alters Ribosomal Function, RNA Splicing, and miRNA Networks: Insights from Multi-Omics Analyses

Abstract

TBC1 domain-containing kinase (TBCK) is an important protein with implications in brain development. Biallelic variants in the TBCK gene are known to cause TBCK-related neurodevelopmental disorder (OMIM #616900) [1], a rare genetic multisystemic disease characterized by developmental delay, variable developmental regression, seizures, and premature death in late childhood for which no cure is currently available. Though previous work has provided a better understanding of the proteins role, the mechanism for how TBCK variants affect gene expression and protein regulation has remained understudied. To better understand the impact of these alterations, and using an unbiased approach, we employed the power of multi-omics to define the cellular consequences at the transcript and protein level. Our comprehensive analysis uncovered significant disruptions in ribosomal and translation-related pathways with widespread alternative splicing defects, and key miRNA changes that validate previously reported molecular findings. This work provides a clearer molecular framework for TBCK dysfunction in TBCK-/- cells and offers a valuable foundation to identify potential therapeutic targets.