Missense mutations in CMS22 patients reveal that PREPL has both enzymatic and non-enzymatic functions-Reference-Cited by-同舟云学术

Missense mutations in CMS22 patients reveal that PREPL has both enzymatic and non-enzymatic functions

Published:2023-12-19 Issue: Volume: Page:
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Monnens Yenthe^ORCID,Theodoropoulou Anastasia^ORCID,Rosier Karen^ORCID,Bhalla Kritika^ORCID,Mahy Alexia^ORCID,Vanhoutte Roeland^ORCID,Meulemans Sandra,Cavani Edoardo^ORCID,Antanasijevic Aleksandar^ORCID,Lemmens Irma^ORCID,Lee Jennifer A.^ORCID,Spellicy Catherin J.,Schroer Richard J.,Maselli Richardo A.,Laverty Chamindra G.^ORCID,Agostinis Patrizia^ORCID,Pagliarini David J.^ORCID,Verhelst Steven^ORCID,Marcaida Maria J.^ORCID,Rochtus Anne^ORCID,Peraro Matteo Dal^ORCID,Creemers John W.M.^ORCID

Abstract

AbstractCongenital myasthenic syndrome-22 (CMS22) is a rare genetic disorder caused by mutations in the prolyl endopeptidase-like (PREPL) gene. Since previous reports only described patients with deletions and nonsense mutations inPREPL, nothing is known about the effect of missense mutations in the pathology of CMS22. In this study, we have characterized missense mutations inPREPLin three CMS22 patients, all with hallmark phenotypes. Biochemical evaluation revealed that these missense mutations do not impair hydrolase activity, thereby challenging the conventional diagnostic criteria. Structural analysis shows that the mutations affect regions most likely involved in intra-protein or protein-protein interactions. Indeed, binding to a selected group of known interactors was differentially reduced for the three mutants. The importance of non-hydrolytic functions of PREPL was investigated in catalytically inactive PREPL p.Ser559Ala cell lines which showed that hydrolytic activity of PREPL is needed for normal mitochondrial function but not for regulating AP1-mediated transport in the trans-Golgi network. In conclusion, these studies show that CMS22 can be caused not only by deletion and truncation of PREPL but also by missense mutations that do not necessarily result in a loss of hydrolytic activity of PREPL.Graphical abstract

Publisher

Cold Spring Harbor Laboratory

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