Elucidating mechanisms underlying the pathogenesis of Hao Fountain Syndrome, a rare disease caused by USP7 variants

SUMMARY Rare genetic diseases affect about 8% of the world's newborn population. Although current technological advances in the exome and genome sequencing of patients with suspected genetic syndromes allow for genetic diagnosis, most rare diseases have no treatment. Many rare disorders remain untreated because the functional follow-up into the pathogenesis lags. This proposal addresses a rare condition, Hao-Fountain syndrome HAFOUS, caused by mutations in the gene coding for the deubiquitinating enzyme USP7. We determined that USP7 is a critical regulator of signals transmitted through the fundamental molecular axis of the extracellular signal-regulated kinases 1 and 2 (ERK1/2) signal pathway. Based on this preliminary data, the central hypothesis of this proposal is that hereditary USP7 variants lead to increased ERK1/2 activity, which, during early morphogenesis, hampers the development of NC-derived tissues, leading to congenital malformation in HAFOUS patients. We will test our hypothesis by pursuing two Specific Aims: 1) Elucidate the effect of HAFOUS variants on ERK1/2 signal transmission in vivo and 2) Assess the effect of USP7 HAFOUS pathogenic variants on embryonic tissue development. To investigate the in vivo effect of HAFOUS variants on the early stages of embryonic development, we will use zebrafish as a vertebrate model. Zebrafish offer distinct advantages for studies of embryonic development, including their transparency and their external and rapid development. The proposed research applies our unique expertise and capacity to integrate zebrafish with biochemical methodologies. In this project, we are poised to uncover a novel mechanistic effect of USP7 mutations on signaling outcomes associated with morphogenesis. The proposed work will establish preliminary data critical for successful future studies focused on the strategies for therapeutic approaches addressing USP7-linked abnormalities.