75 - Reduced TBCK a Potential Cause of Bone Dysmorphology in a Mouse Model of Pediatric Neurodegeneration

Poster Board Number: 75
There are separate poster presentation times for odd and even posters.
Odd poster #s – first hour
Even poster #s – second hour

Abstract Body : In 2017, we and others discovered mutations in TBC1 Domain Containing Kinase (TBCK) cause a multisystem disorder that is characterized by pediatric neurodegeneration. Recently, through clinical analysis of dozens of children with this ultra-rare disorder we have also determined that there is a bone fragility phenotype resembling severe osteoporosis that is far more pronounced than would be predicted by just hypotonia/deconditioning as well as abnormal craniofacial form. To study this devastating and fatal disease, we have created a mouse knockout model that replicates the neurologic phenotype of the disorder. Though tbck-/- mice are unlikely to survive to adulthood, we have begun to investigate the impact of TBCK loss in heterozygous mice (tbck+/-) relative to their fully functioning TBCK (tbck+/+) littermates. We hypothesize that though TBCK-encephaloneuropathy is only associated with compete loss of TBCK protein, direct and/or indirect effects of this mutation may impact bone development and health. In an adult cohort of heterozygous (tbck+/-) and unaffected tbck+/+ mice (n=7/genotype), we found no difference in skull endocast volume between genotypes, using uCT and 3D Slicer software. However, cephalometric analysis indicated differences in tbck+/- skulls. Heterozygous calvaria were altered with a wider and longer shape as compared to unaffected littermates. Additionally, histomorphometric investigations showed altered suture morphology. The width and area of the sagittal suture from tbck+/- mice were greater as compared to unaffected tbck+/+ littermates, suggesting altered growth in the anteroposterior dimension. Our results confirm occurrence of system-wide effects of TBCK, specifically in bone. While the function of TBCK remains to be fully characterized, our current work is a first step in establishing a novel pathway link between this neurodegeneration causing mutation and systemic bone health. As negative bone phenotypes have been noted in over half of the documented TBCK- encephaloneuropathy patients, we aim to continue this research to identify potential mechanisms of TBCK-related craniofacial abnormalities in a hope that we will find potential therapeutic interventions for this vulnerable patient population.