Journal Article

A novel mouse model of rare neurodevelopmental disorder, TBCK Syndrome

Melendez-Perez, Ashley J, Black, Aaron, Diaz-Rosado, Abdias, O'Brien, W Timothy, Wang, Xiao-Min, Katsura, Kaitlin A, Angireddy, Rajesh, Worthington, Kaitlyn E, Lubin, Emily E, Bhoj, Elizabeth J K, Gonzalez, Elizabeth M, Ciesielski, Brianna, Durham, Emily L, Layo-Carris, Dana E, Abdalla, Kelly J, Smith, Sarina M, Nair, Divya

2026

Overview

TBCK Syndrome is a rare Mendelian disorder caused by variants in the gene. Although symptoms affect multiple organ systems, hallmark features include intellectual and developmental disability, craniofacial differences, hypotonia, and premature death. At the cellular level, TBCK has been implicated in mTOR signaling, autophagy, mitophagy, and mRNA trafficking; however, the mechanisms underlying disease onset and progression remain unclear. To address this gap, we characterized a mouse model of TBCK Syndrome. These mice lack exon 5 of the gene, resulting in a whole-body knockout of , modeling the most severe known variant. We performed a comprehensive battery of developmental assays, along with microcomputed tomography and histological analyses, which revealed systemic alterations consistent with those observed in affected individuals. Notably, phenotypic changes arising from Tbck loss emerge early and are detectable in the brain, indicating a primary neurodevelopmental origin of disease pathology. Rigorous characterization of this Tbck-deficient mouse establishes the first platform to investigate disease mechanisms and provides a foundation for preclinical evaluation of gene and targeted pharmacological therapy strategies.

• Publisher: Cold Spring Harbor Laboratory,Cold Spring Harbor Laboratory Preprints
• Subject: Genetics