The motivation behind the work of the Bhoj lab is to provide answers to families about their child’s medical issues and work towards targeted therapies for genetic disorders.  There are many thousands of children who are suspected to have a genetic disorder, but remain without a diagnosis, even after expert evaluation. Many of these children have yet-undiscovered genetic syndromes, and the Bhoj lab uses advanced sequencing technology to identify these novel syndromes. Two of the syndromes we now focus on are caused by disruption of Histone 3.3 (H3F3A and H3F3B) and TBC1 domain-containing Kinase (TBCK).

Histone 3.3 is one of the replacement histones, and is vital for appropriate cell division, transcription, and many other processes. Somatic variants cause a variety of cancer, including pediatric glioblastoma. Our laboratory described a pediatric neurodegenerative condition caused by germline variants in H3F3A and H3F3B, which both code for the Histone 3.3 protein. Using patient cells, mouse models, and iPSC cells, we are learning more about why these genetic variant cause this disease. Our goal is to be able to learn enough about the pathogenesis of the disorder to develop the first targeted therapies for this progressive neurologic disorder.

Our laboratory was also instrumental in the discovery of TBC1 domain-containing Kinase (TBCK) as a cause of progressive neurodegeneration in children. Very little was known about the role of TBCK, and we are working to learn more about how TBCK works in healthy tissues and contributes to neurodegeneration. We are using patient cells and model organisms to understand how the loss of this protein disrupts normal neurologic development. Our early data suggested the mTOR pathway was downregulated in these patients, and we showed that leucine, an amino acid, is a potential targeted therapy. We are now working on leucine and related compounds in animal models of the disease and hope to start a human trial.

Projects:

  1. Novel human gene discovery in pediatric patients with undiagnosed syndromes
  2. Pathogenesis and therapy development in patients with Histone 3.3-related neurologic dysfunction – both animal models and human cells.
  3. Role of TBCK in normal and abnormal neurodevelopment, leucine and related compounds to treat TBCK-related neurodegeneration.

Please contact Elizabeth Bhoj if you have any questions or an interest to learn more about the lab – we’re always hoping to grow the lab with others who have a passion for helping children with rare genetic disorders.