Understanding the effect of Hao-Fountain syndrome-causing mutations on neuronal development

ABSTRACT Hao-Fountain syndrome is a newly identified rare pediatric neurodevelopmental disorder caused by deletions and mutations of the USP7 gene. The molecular mechanisms and pathophysiology of the disease remain poorly understood, preventing the development of potential treatments for Hao-Fountain patients. USP7 is a

deubiquitinating enzyme implicated in the maintenance of protein homeostasis, stem cell identity, self-renewal, and control of dendritic branching in primary neurons. A model system has not yet been created but is indispensable for understanding the disease and for the evaluation of potential personalized therapies for Hao-

Fountain Syndrome. In this proposal, we will create the first human-based cellular model of Hao-Fountain to test the effect of disease-linked mutations on the enzymatic function of USP7 (Aim 1), and on neuron differentiation potential and morphology (Aim 2). The patient-derived induced pluripotent stem cells will be differentiated into

cortical neurons to create the Hao-Fountain model system that will be shared with the greater community to accelerate the understanding of this newly discovered and devastating disease.