PMID- 24183932
OWN - NLM
STAT- MEDLINE
DCOM- 20150112
LR  - 20140512
IS  - 1873-264X (Electronic)
IS  - 0731-7085 (Linking)
VI  - 93
DP  - 2014 May
TI  - Metabolic expressivity of human genetic variants: NMR metabotyping of MEN1 
      pathogenic mutants.
PG  - 118-24
LID - S0731-7085(13)00459-7 [pii]
LID - 10.1016/j.jpba.2013.09.029 [doi]
AB  - 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.
CI  - Copyright (c) 2013 Elsevier B.V. All rights reserved.
FAU - Blaise, Benjamin J
AU  - Blaise BJ
AD  - Universite de Lyon, Institut des Sciences Analytiques CNRS/ENS Lyon/UCB Lyon 1, 
      Centre de RMN a Tres Hauts Champs, 5 rue de la Doua, 69100 Villeurbanne, France.
FAU - Lopez, Claire
AU  - Lopez C
AD  - Universite de Lyon, Institut des Sciences Analytiques CNRS/ENS Lyon/UCB Lyon 1, 
      Centre de RMN a Tres Hauts Champs, 5 rue de la Doua, 69100 Villeurbanne, France.
FAU - Vercherat, Cecile
AU  - Vercherat C
AD  - Inserm U1052/CNRS UMR5286/Universite de Lyon, Lyon1 UMR-S1052, Cancer Research 
      Center of Lyon, Lyon F-69008, France.
FAU - Lacheretz-Bernigaud, Annie
AU  - Lacheretz-Bernigaud A
AD  - Inserm U1052/CNRS UMR5286/Universite de Lyon, Lyon1 UMR-S1052, Cancer Research 
      Center of Lyon, Lyon F-69008, France.
FAU - Bayet-Robert, Mathilde
AU  - Bayet-Robert M
AD  - Universite de Lyon, Institut des Sciences Analytiques CNRS/ENS Lyon/UCB Lyon 1, 
      Centre de RMN a Tres Hauts Champs, 5 rue de la Doua, 69100 Villeurbanne, France.
FAU - Rezig, Lamya
AU  - Rezig L
AD  - Universite de Lyon, Institut des Sciences Analytiques CNRS/ENS Lyon/UCB Lyon 1, 
      Centre de RMN a Tres Hauts Champs, 5 rue de la Doua, 69100 Villeurbanne, France; 
      Inserm U1052/CNRS UMR5286/Universite de Lyon, Lyon1 UMR-S1052, Cancer Research 
      Center of Lyon, Lyon F-69008, France.
FAU - Scoazec, Jean-Yves
AU  - Scoazec JY
AD  - Inserm U1052/CNRS UMR5286/Universite de Lyon, Lyon1 UMR-S1052, Cancer Research 
      Center of Lyon, Lyon F-69008, France.
FAU - Calender, Alain
AU  - Calender A
AD  - Inserm U1052/CNRS UMR5286/Universite de Lyon, Lyon1 UMR-S1052, Cancer Research 
      Center of Lyon, Lyon F-69008, France.
FAU - Emsley, Lyndon
AU  - Emsley L
AD  - Universite de Lyon, Institut des Sciences Analytiques CNRS/ENS Lyon/UCB Lyon 1, 
      Centre de RMN a Tres Hauts Champs, 5 rue de la Doua, 69100 Villeurbanne, France.
FAU - Elena-Herrmann, Benedicte
AU  - Elena-Herrmann B
AD  - Universite de Lyon, Institut des Sciences Analytiques CNRS/ENS Lyon/UCB Lyon 1, 
      Centre de RMN a Tres Hauts Champs, 5 rue de la Doua, 69100 Villeurbanne, France. 
      Electronic address: benedicte.elena@ens-lyon.fr.
FAU - Cordier-Bussat, Martine
AU  - Cordier-Bussat M
AD  - Inserm U1052/CNRS UMR5286/Universite de Lyon, Lyon1 UMR-S1052, Cancer Research 
      Center of Lyon, Lyon F-69008, France. Electronic address: 
      martine.cordier-bussat@inserm.fr.
LA  - eng
PT  - Journal Article
DEP - 20131016
PL  - England
TA  - J Pharm Biomed Anal
JT  - Journal of pharmaceutical and biomedical analysis
JID - 8309336
RN  - 0 (MEN1 protein, human)
RN  - 0 (Proto-Oncogene Proteins)
SB  - IM
MH  - Animals
MH  - Feasibility Studies
MH  - Gene Expression Regulation, Neoplastic
MH  - Humans
MH  - Magnetic Resonance Spectroscopy/*methods
MH  - *Models, Biological
MH  - Multiple Endocrine Neoplasia Type 1/*genetics
MH  - Mutation, Missense
MH  - Proto-Oncogene Proteins/*genetics
MH  - Rats
OTO - NOTNLM
OT  - Endocrine cancer
OT  - HR-MAS NMR
OT  - MEN1
OT  - Menin
OT  - Metabolomics
EDAT- 2013/11/05 06:00
MHDA- 2015/01/13 06:00
CRDT- 2013/11/05 06:00
PHST- 2013/07/01 00:00 [received]
PHST- 2013/09/23 00:00 [revised]
PHST- 2013/09/25 00:00 [accepted]
PHST- 2013/11/05 06:00 [entrez]
PHST- 2013/11/05 06:00 [pubmed]
PHST- 2015/01/13 06:00 [medline]
AID - S0731-7085(13)00459-7 [pii]
AID - 10.1016/j.jpba.2013.09.029 [doi]
PST - ppublish
SO  - J Pharm Biomed Anal. 2014 May;93:118-24. doi: 10.1016/j.jpba.2013.09.029. Epub 
      2013 Oct 16.