Missense variants in CMS22 patients reveal that PREPL has both enzymatic and nonenzymatic functions.

ABSTRACT: Congenital myasthenic syndrome-22 (CMS22, OMIM 616224) is a rare genetic disorder caused by deleterious genetic variation in the prolyl endopeptidase-like (PREPL) gene. Previous reports have described patients with deletions and nonsense variants in PREPL, but nothing is known about the effect of missense variants in the pathology of CMS22. In this study, we have functionally characterized missense variants in PREPL from 3 patients with CMS22, all with hallmark phenotypes. Biochemical evaluation revealed that these missense variants do not impair hydrolase activity, thereby challenging the conventional diagnostic criteria and disease mechanism. Structural analysis showed that the variants affect regions most likely involved in intraprotein or protein-protein interactions. Indeed, binding t

SUBMITTER: Monnens Y 

PROVIDER: S-EPMC11385081 | biostudies-literature | 2024 Sep

REPOSITORIES: biostudies-literature