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Missense variants in CMS22 patients reveal that PREPL has both enzymatic and nonenzymatic functions.
Monnens, Yenthe; Theodoropoulou, Anastasia; Rosier, Karen; Bhalla, Kritika; Mahy, Alexia; Vanhoutte, Roeland; Meulemans, Sandra; Cavani, Edoardo; Antanasijevic, Aleksandar; Lemmens, Irma; Lee, Jennifer A; Spellicy, Catherine J; Schroer, Richard J; Maselli, Ricardo A; Laverty, Chamindra G; Agostinis, Patrizia; Pagliarini, David J; Verhelst, Steven; Marcaida, Maria J; Rochtus, Anne; Dal Peraro, Matteo; Creemers, John Wm.
Afiliación
  • Monnens Y; Laboratory for Biochemical Neuroendocrinology, Department of Human Genetics, KU Leuven, Leuven, Belgium.
  • Theodoropoulou A; Laboratory for Biomolecular Modeling, Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
  • Rosier K; Laboratory for Biochemical Neuroendocrinology, Department of Human Genetics, KU Leuven, Leuven, Belgium.
  • Bhalla K; Laboratory for Biochemical Neuroendocrinology, Department of Human Genetics, KU Leuven, Leuven, Belgium.
  • Mahy A; Laboratory for Biochemical Neuroendocrinology, Department of Human Genetics, KU Leuven, Leuven, Belgium.
  • Vanhoutte R; Laboratory for Chemical Biology, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
  • Meulemans S; Laboratory for Biochemical Neuroendocrinology, Department of Human Genetics, KU Leuven, Leuven, Belgium.
  • Cavani E; Laboratory for Biomolecular Modeling, Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
  • Antanasijevic A; Global Health Institute, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
  • Lemmens I; VIB-UGent Center for Medical Biotechnology, Department of Biomolecular Medicine, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium.
  • Lee JA; Greenwood Genetic Center, South Carolina, USA.
  • Spellicy CJ; Greenwood Genetic Center, South Carolina, USA.
  • Schroer RJ; Greenwood Genetic Center, South Carolina, USA.
  • Maselli RA; Department of Neurology, UCD, Sacramento, California, USA.
  • Laverty CG; Department of Neuroscience, UCSD, San Diego, California, USA.
  • Agostinis P; Laboratory for Cell death Research & Therapy, VIB, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
  • Pagliarini DJ; Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin, USA.
  • Verhelst S; Laboratory for Chemical Biology, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
  • Marcaida MJ; Laboratory for Biomolecular Modeling, Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
  • Rochtus A; UZ Leuven University Hospital, Leuven, Belgium.
  • Dal Peraro M; Laboratory for Biomolecular Modeling, Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
  • Creemers JW; Laboratory for Biochemical Neuroendocrinology, Department of Human Genetics, KU Leuven, Leuven, Belgium.
JCI Insight ; 9(17)2024 Sep 10.
Article en En | MEDLINE | ID: mdl-39078710
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 to a selected group of known interactors was differentially reduced for the 3 variants. The importance of nonhydrolytic 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 transgolgi network. In conclusion, these studies showed that CMS22 can be caused not only by deletion and truncation of PREPL but also by missense variants that do not necessarily result in a loss of hydrolytic activity of PREPL.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Mutación Missense / Síndromes Miasténicos Congénitos / Prolil Oligopeptidasas Límite: Female / Humans / Male Idioma: En Revista: JCI Insight Año: 2024 Tipo del documento: Article País de afiliación: Bélgica Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Mutación Missense / Síndromes Miasténicos Congénitos / Prolil Oligopeptidasas Límite: Female / Humans / Male Idioma: En Revista: JCI Insight Año: 2024 Tipo del documento: Article País de afiliación: Bélgica Pais de publicación: Estados Unidos