title: p.Ala541Thr variant of MEN1 gene: a non deleterious polymorphism or a pathogenic mutation?
abstract: BACKGROUND
  Multiple Endocrine Neoplasia Type 1 (MEN1) is an autosomal dominant inherited syndrome, related to mutations in the MEN1 gene. Controversial data suggest that the nonsynonymous p.Ala541Thr variant, usually considered as a non-pathogenic polymorphism, may be associated with an increased risk of MEN1-related lesions in carriers.
  
  
  OBJECTIVE
  The aim of this study was to evaluate the pathogenic influence of the p.Ala541Thr variant on clinical and functional outcomes.
  
  
  METHODS
  We analysed a series of 55 index patients carrying the p.Ala541Thr variant. Their clinical profile was compared to that of 117 MEN1 patients. The biological impact of the p.Ala541Thr variant on cell growth was additionally investigated on menin-deficient Leydig cell tumour (LCT)10 cells generated from Men1+/Men1- heterozygous knock-out mice, and compared with wild type (WT).
  
  
  RESULTS
  The mean age at first appearance of endocrine lesions was similar in both p.Ala541Thr carriers and MEN1 patients, but no p.Ala541Thr patient had more than one cardinal MEN1 lesion at initial diagnosis. A second MEN1 lesion was diagnosed in 13% of MEN1 patients and in 7% of p.Ala541Thr carriers in the year following preliminary diagnosis. Functional studies on LCT10 cells showed that overexpression of the p.Ala541Thr variant did not inhibit cell growth, which is in direct contrast to results obtained from investigation of WT menin protein.
  
  
  CONCLUSIONS
  Taken together, these data raise the question of a potential pathogenicity of the p.Ala541Thr missense variant of menin that commonly occurs within the general population. Additional studies are required to investigate whether it may be involved in a low-penetrance MEN1 phenotype.
authors.affiliation: Fédération d'endocrinologie du Pôle Lyon-Est, université Lyon 1, groupement hospitalier Est, hospices civils de Lyon, 59, boulevard Pinel, 69677 Bron cedex, France; UMR 5201 génétique, signalisation et cancer, centre Léon-Bérard, 69008 Lyon, France. Electronic address: cnozieres@yahoo.fr.
authors.forename: Cecile
authors.initials: C
authors.lastname: Nozières
authors.affiliation: UMR 5201 génétique, signalisation et cancer, centre Léon-Bérard, 69008 Lyon, France.
authors.forename: Chang-Xian
authors.initials: CX
authors.lastname: Zhang
authors.affiliation: Service de génétique, hôpital européen Georges-Pompidou, Assistance publique-Hôpitaux de Paris, 75015 Paris, France; Faculté de médecine, université Paris-Descartes, Sorbonne Paris-Cité, 75006 Paris, France; Inserm, UMR970, Paris cardiovascular research center, 75015 Paris, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Buffet
authors.affiliation: Laboratoire de génétique moléculaire, hôpital Édouard-Herriot, bâtiment B7, 69347 Lyon cedex 03, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Dupasquier
authors.affiliation: Service de génétique, hôpital européen Georges-Pompidou, Assistance publique-Hôpitaux de Paris, 75015 Paris, France; Faculté de médecine, université Paris-Descartes, Sorbonne Paris-Cité, 75006 Paris, France; Inserm, UMR970, Paris cardiovascular research center, 75015 Paris, France.
authors.forename: Rosa
authors.initials: R
authors.lastname: Vargas-Poussou
authors.affiliation: Laboratoire d'oncogénétique, hôpital Cochin, 75679 Paris cedex 14, France.
authors.forename: Marine
authors.initials: M
authors.lastname: Guillaud-Bataille
authors.affiliation: Inserm U 865, université Claude-Bernard-Lyon 1, 7-11, rue Guillaume-Paradin, 69372 Lyon cedex 08, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Cordier-Bussat
authors.affiliation: Service de gastro-entérologie, hôpital Beaujon, 100, boulevard du Général-Leclerc, 92110 Clichy, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Ruszniewski
authors.affiliation: Service d'endocrinologie, faculté de médecine, université Paris VI, hôpital Saint-Antoine, Assistance publique-Hôpitaux de Paris, 184, rue du Faubourg Saint-Antoine, 75571 Paris cedex 12, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Christin-Maitre
authors.affiliation: Clinique endocrinologie, maladies métaboliques et nutrition, hôpital de l'Hôtel-Dieu, CHU de Nantes, place Alexis-Ricordeau, BP 100, 44093 Nantes cedex 1, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Murat
authors.affiliation: Service d'endocrinologie et maladies métaboliques, faculté de médecine, université Paris-Descartes, hôpital Cochin, Assistance publique-Hôpitaux de Paris, 75679 Paris cedex 14, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Groussin
authors.affiliation: Service d'endocrinologie, maladies métaboliques et nutrition, hôpital Larrey, 31059 Toulouse cedex, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Vezzosi
authors.affiliation: Clinique Marc-Linquette, 59037 Lille, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Cardot-Bauters
authors.affiliation: Service d'anatomo-pathologie, hôpital Édouard-Herriot, place d'Arsonval, 69003 Lyon, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Hervieu
authors.affiliation: Service d'anatomo-pathologie, hôpital Édouard-Herriot, place d'Arsonval, 69003 Lyon, France.
authors.forename: Marie-Odile
authors.initials: MO
authors.lastname: Joly
authors.affiliation: UMR 5201 génétique, signalisation et cancer, centre Léon-Bérard, 69008 Lyon, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Giraud
authors.affiliation: Service de génétique moléculaire, pôle de pathologie biologie, Eurasanté, CHRU de Lille, 59000 Lille, France.
authors.forename: Marie-Françoise
authors.initials: MF
authors.lastname: Odou
authors.affiliation: Service de génétique, hôpital européen Georges-Pompidou, Assistance publique-Hôpitaux de Paris, 75015 Paris, France; Faculté de médecine, université Paris-Descartes, Sorbonne Paris-Cité, 75006 Paris, France; Inserm, UMR970, Paris cardiovascular research center, 75015 Paris, France.
authors.forename: Anne-Paule
authors.initials: AP
authors.lastname: Gimenez-Roqueplo
authors.affiliation: Service de chirurgie endocrinienne, hôpital du Bocage, 2, boulevard de Lattre-de-Tassigny, 21034 Dijon, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Goudet
authors.affiliation: Fédération d'endocrinologie du Pôle Lyon-Est, université Lyon 1, groupement hospitalier Est, hospices civils de Lyon, 59, boulevard Pinel, 69677 Bron cedex, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Borson-Chazot
authors.affiliation: UMR 5201 génétique, signalisation et cancer, centre Léon-Bérard, 69008 Lyon, France; Laboratoire de génétique moléculaire, hôpital Édouard-Herriot, bâtiment B7, 69347 Lyon cedex 03, France. Electronic address: alain.calender@chu-lyon.fr.
authors.forename: Alain
authors.initials: A
authors.lastname: Calender
mesh_terms: D000236:Adenoma / Q000235:genetics; D000328:Adult; D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D006579:Heterozygote; D006801:Humans; D006961:Hyperparathyroidism / Q000235:genetics; D007984:Leydig Cell Tumor / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D018761:Multiple Endocrine Neoplasia Type 1 / Q000235:genetics*; D009154:Mutation; D010641:Phenotype; D010911:Pituitary Neoplasms / Q000235:genetics; D011110:Polymorphism, Genetic / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics*; D014162:Transfection
chemical_list: C105373:MEN1 protein, human; C484898:Men1 protein, mouse; D011518:Proto-Oncogene Proteins
keywords: Multiple endocrine neoplasia type 1; Mutation; Néoplasie endocrinienne multiple de type 1; Penetrance; Polymorphism; Polymorphisme; Predisposition; Prédisposition; Pénétrance