Metabolic expressivity of human genetic variants: NMR metabotyping of MEN1 pathogenic mutants
| Autor: | Jean-Yves Scoazec, Alain Calender, Mathilde Bayet-Robert, Bénédicte Elena-Herrmann, Benjamin J. Blaise, Annie Lacheretz-Bernigaud, Martine Cordier-Bussat, Lyndon Emsley, Claire Lopez, Lamya Rezig, Cécile Vercherat |
|---|---|
| Přispěvatelé: | NMR Methods for Metabolism - Methodes RMN en métabolomique, Institut des Sciences Analytiques ( ISA ), École normale supérieure - Lyon ( ENS Lyon ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ) -École normale supérieure - Lyon ( ENS Lyon ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ), Tumeurs endocrines digestives : mécanismes de la tumorigenèse et de la progression tumorale, Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de Recherche en Cancérologie de Lyon ( CRCL ), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire Central d'Anatomie et de Cytologie Pathologiques [Hôpital Edouard Herriot - HCL], Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon ( HCL ), Solid-State NMR Methods for Materials - Méthodes de RMN à l'état solide pour les matériaux, ISA NMR Methods for Metabolism - Methodes RMN en métabolomique (2014-2018), Institut des Sciences Analytiques (ISA), Institut de Chimie du CNRS (INC)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre Léon Bérard [Lyon]-Hospices Civils de Lyon (HCL) |
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
endocrine system
Magnetic Resonance Spectroscopy endocrine system diseases Clinical Biochemistry Mutant Mutation Missense Endocrine cancer Pharmaceutical Science Models Biological Analytical Chemistry Metabolomics [CHIM.ANAL]Chemical Sciences/Analytical chemistry Proto-Oncogene Proteins Drug Discovery Genetic variation Multiple Endocrine Neoplasia Type 1 MAGNETIC-RESONANCE SPECTROSCOPY Animals Humans MEN1 Gene Spectroscopy Genetics Chemistry Wild type METABONOMICS Menin Phenotype TUMORS Rats 3. Good health Gene Expression Regulation Neoplastic CELLS HR-MAS NMR Feasibility Studies [ CHIM.ANAL ] Chemical Sciences/Analytical chemistry Functional genomics |
| Zdroj: | Journal of Pharmaceutical and Biomedical Analysis Journal of Pharmaceutical and Biomedical Analysis, Elsevier, 2014, 93, pp.118-124. 〈10.1016/j.jpba.2013.09.029〉 Journal of Pharmaceutical and Biomedical Analysis, Elsevier, 2014, 93, pp.118-124. ⟨10.1016/j.jpba.2013.09.029⟩ |
| ISSN: | 0731-7085 |
| DOI: | 10.1016/j.jpba.2013.09.029〉 |
| Popis: | Functional consequences of mutations in predisposition genes for familial cancer syndromes remain often elusive, especially when the corresponding gene products play pleiotropic functions and interact with numerous partners. Understanding the consequences of these genetic alterations requires access to their functional effects at the phenotypic level. Nuclear magnetic resonance (NMR) has emerged as a promising functional genomics probe, through its ability to monitor the consequences of genetic variations at the biochemical level. Here, we determine by NMR the metabolic perturbations associated with different disease-related mutations in the MEN1 gene, responsible for the multiple endocrine neoplasia syndrome, type 1 (MEN1), an example of hereditary cancer. The MEN1 gene encodes the Menin protein. Based on a cellular model that allows exogenous overexpression of either the wild type (WT) Menin protein or disease-related variant forms, we evaluate the feasibility of using metabolic profiles to discriminate cells with WT versus variant Menin overexpression. High-resolution magic angle spinning (HRMAS) NMR of whole cells allows to determine the metabolic features associated with overexpression of WT Menin as compared to the one of six different missense variants observed in MEN1 patients. We then identify several statistically significant individual metabolites associated with the metabolic signature of pathogenic versus WT variants. Whether such a metabolic phenotyping approach using cell lines could be exploited as a functional test in a human genetic cancer syndrome is further discussed. (C) 2013 Elsevier B.V. All rights reserved. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect