Investigating the role of BCKDK in neurodevelopmental disorders through a novel mouse model

Ut Southwestern Medical Center, Dallas TX

Investigators

Abstract

Project Summary Neurodevelopmental disorders (NDDs) affecting cognitive and social abilities are a phenotypically and genetically heterogeneous group of conditions. Understanding the molecular mechanisms underlying these disorders is crucial for the development of targeted therapies. Loss-of-function mutations in the gene BCKDK, encoding the branched-chain a-ketoacid dehydrogenase kinase, result in autism spectrum disorder (ASD) and epilepsy. Conversely, duplications of chromosome 16p11.2 spanning the BCKDK locus have been identified in patients with a spectrum of neurodevelopmental phenotypes, including developmental delay, speech and language abnormalities, intellectual disability, ASD, and microcephaly. However, it is not known whether the neurodevelopmental phenotypes arise due to an increased copy of BCKDK or how BCKDK overexpression mediates these phenotypes. The goal of this proposal is to generate a transgenic mouse model overexpressing BCKDK, and to characterize the resulting neurobehavioral phenotypes. Our proposal will develop the first mouse model of BCKDK overexpression and test, for the first time, the link between BCKDK overexpression and NDDs. Results from our studies will ?illuminate? an understudied protein kinase, BCKDK, by providing animal model- based evidence for disease relevance and generating reagents and data for the scientific community.