Dissecting the role of the KLHL17 gene in the molecular pathogenesis of the West syndrome

This project has been funded thanks to the Joint Call Fondazione Cariplo and Fondazione Telethon 2022

Developmental and epileptic encephalopathies (DEE) refer to a group of infantile epilepsies. Most DEEs begin early in life, are often resistant to anti-epileptic drugs, and the developmental outcome is poor. This project will focus on the West syndrome (WS), which is characterized by the association of clusters of axial spasms and an hypsarrhythmic interictal EEG pattern. WS has a multifactorial etiology, and the underlying pathophysiology remains largely unknown. For this reason, molecular studies are urgently needed to develop innovative therapeutic approaches. In particular, the dissection of the pathogenic mechanisms underlying specific genetic defects is of great importance in a medium-long term perspective that foresees precision medicine tailored to treat patients carrying defined gene alterations. In this project, we focus on KLHL17 gene, which was found associated in a cohort of WS patients and whose function is unknown. Very recently, mutations in KLHL17 was found in individuals with intellectual disability, further highlighting its importance in the pathophysiology of brain development. We take an interdisciplinary approach to interrogate the molecular function of KLHL17 in the cerebral cortex. We will study its role in the development of synapses, the elementary functional units of the brain, which are functionally impaired in a wide spectrum of neurological disorders. Using unbiased proteomics and hypothesis-driven approaches, we will characterize the pathways that are regulated by KLHL17. The innovative and original nature of this research program will uncover novel pathogenic insights into the development of WS and hopefully offer new therapeutic perspectives to treat this severe pediatric disease.