title: Metabolic expressivity of human genetic variants: NMR metabotyping of MEN1 pathogenic mutants.
abstract: 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.
authors.affiliation: Université de Lyon, Institut des Sciences Analytiques CNRS/ENS Lyon/UCB Lyon 1, Centre de RMN à Très Hauts Champs, 5 rue de la Doua, 69100 Villeurbanne, France.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Blaise
authors.affiliation: Université de Lyon, Institut des Sciences Analytiques CNRS/ENS Lyon/UCB Lyon 1, Centre de RMN à Très Hauts Champs, 5 rue de la Doua, 69100 Villeurbanne, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Lopez
authors.affiliation: Inserm U1052/CNRS UMR5286/Université de Lyon, Lyon1 UMR-S1052, Cancer Research Center of Lyon, Lyon F-69008, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Vercherat
authors.affiliation: Inserm U1052/CNRS UMR5286/Université de Lyon, Lyon1 UMR-S1052, Cancer Research Center of Lyon, Lyon F-69008, France.
authors.forename: Annie
authors.initials: A
authors.lastname: Lacheretz-Bernigaud
authors.affiliation: Université de Lyon, Institut des Sciences Analytiques CNRS/ENS Lyon/UCB Lyon 1, Centre de RMN à Très Hauts Champs, 5 rue de la Doua, 69100 Villeurbanne, France.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Bayet-Robert
authors.affiliation: Université de Lyon, Institut des Sciences Analytiques CNRS/ENS Lyon/UCB Lyon 1, Centre de RMN à Très Hauts Champs, 5 rue de la Doua, 69100 Villeurbanne, France; Inserm U1052/CNRS UMR5286/Université de Lyon, Lyon1 UMR-S1052, Cancer Research Center of Lyon, Lyon F-69008, France.
authors.forename: Lamya
authors.initials: L
authors.lastname: Rezig
authors.affiliation: Inserm U1052/CNRS UMR5286/Université de Lyon, Lyon1 UMR-S1052, Cancer Research Center of Lyon, Lyon F-69008, France.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Scoazec
authors.affiliation: Inserm U1052/CNRS UMR5286/Université de Lyon, Lyon1 UMR-S1052, Cancer Research Center of Lyon, Lyon F-69008, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Calender
authors.affiliation: Université de Lyon, Institut des Sciences Analytiques CNRS/ENS Lyon/UCB Lyon 1, Centre de RMN à Très Hauts Champs, 5 rue de la Doua, 69100 Villeurbanne, France.
authors.forename: Lyndon
authors.initials: L
authors.lastname: Emsley
authors.affiliation: Université de Lyon, Institut des Sciences Analytiques CNRS/ENS Lyon/UCB Lyon 1, Centre de RMN à Très Hauts Champs, 5 rue de la Doua, 69100 Villeurbanne, France. Electronic address: benedicte.elena@ens-lyon.fr.
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Elena-Herrmann
authors.affiliation: Inserm U1052/CNRS UMR5286/Université de Lyon, Lyon1 UMR-S1052, Cancer Research Center of Lyon, Lyon F-69008, France. Electronic address: martine.cordier-bussat@inserm.fr.
authors.forename: Martine
authors.initials: M
authors.lastname: Cordier-Bussat
mesh_terms: D000818:Animals; D005240:Feasibility Studies; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008954:Models, Biological; D018761:Multiple Endocrine Neoplasia Type 1 / Q000235:genetics*; D020125:Mutation, Missense; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051381:Rats
chemical_list: C105373:MEN1 protein, human; D011518:Proto-Oncogene Proteins
keywords: Endocrine cancer; HR-MAS NMR; MEN1; Menin; Metabolomics