Unraveling the pathology of the novel congenital myasthenic syndrome-22 (CMS22) and investigation of molecular links with Prader-Willi syndrome.

Inactivation of PREPL, a gene located on chromosome 2 encoding the prolyl endopeptidase-like (PREPL) protein, leads to the novel congenital myasthenic syndrome-22 (CMS22). This syndrome is characterized by hypotonia and growth impairment in children. Later, CMS22 develops into hyperphagia and obesity. These phenotypes share striking similarities with Prader-Willi syndrome (PWS) and most patients are initially misdiagnosed with PWS. However, much of the cellular function of PREPL and its molecular connection with PWS remains unknown. Therefore, this project will focus on unraveling PREPL’s cellular function in cell culture models and knockout mice. In addition, I will assess the effect of patient point mutations on PREPL’s catalytic and non-catalytic functions as point mutations are understudied, but most common, in CMS22 patients. Furthermore, I will investigate molecular links between CMS22 and PWS and, in collaboration with Dr. Florian Merkle (University of Cambridge, UK), I will unravel PREPL’s function in hypothalamic neurons, a main cell type involved in metabolic dysregulation of both diseases. Clarifying the cellular function of PREPL and the contribution of PREPL in PWS will be a breakthrough which will lead to improved diagnosis and novel treatment plans.