Cecile Nozières1, Chang-Xian Zhang2, Alexandre Buffet3, Stéphanie Dupasquier4, Rosa Vargas-Poussou3, Marine Guillaud-Bataille5, Martine Cordier-Bussat6, Philippe Ruszniewski7, Sophie Christin-Maitre8, Arnaud Murat9, Lionel Groussin10, Delphine Vezzosi11, Catherine Cardot-Bauters12, Valérie Hervieu13, Marie-Odile Joly13, Sophie Giraud2, Marie-Françoise Odou14, Anne-Paule Gimenez-Roqueplo3, Pierre Goudet15, Françoise Borson-Chazot16, Alain Calender17. 1. 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. 2. UMR 5201 génétique, signalisation et cancer, centre Léon-Bérard, 69008 Lyon, France. 3. 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. 4. Laboratoire de génétique moléculaire, hôpital Édouard-Herriot, bâtiment B7, 69347 Lyon cedex 03, France. 5. Laboratoire d'oncogénétique, hôpital Cochin, 75679 Paris cedex 14, France. 6. Inserm U 865, université Claude-Bernard-Lyon 1, 7-11, rue Guillaume-Paradin, 69372 Lyon cedex 08, France. 7. Service de gastro-entérologie, hôpital Beaujon, 100, boulevard du Général-Leclerc, 92110 Clichy, France. 8. 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. 9. Clinique endocrinologie, maladies métaboliques et nutrition, hôpital de l'Hôtel-Dieu, CHU de Nantes, place Alexis-Ricordeau, BP 100, 44093 Nantes cedex 1, France. 10. Service d'endocrinologie et maladies métaboliques, faculté de médecine, université Paris-Descartes, hôpital Cochin, Assistance publique-Hôpitaux de Paris, 75679 Paris cedex 14, France. 11. Service d'endocrinologie, maladies métaboliques et nutrition, hôpital Larrey, 31059 Toulouse cedex, France. 12. Clinique Marc-Linquette, 59037 Lille, France. 13. Service d'anatomo-pathologie, hôpital Édouard-Herriot, place d'Arsonval, 69003 Lyon, France. 14. Service de génétique moléculaire, pôle de pathologie biologie, Eurasanté, CHRU de Lille, 59000 Lille, France. 15. Service de chirurgie endocrinienne, hôpital du Bocage, 2, boulevard de Lattre-de-Tassigny, 21034 Dijon, France. 16. Fédération d'endocrinologie du Pôle Lyon-Est, université Lyon 1, groupement hospitalier Est, hospices civils de Lyon, 59, boulevard Pinel, 69677 Bron cedex, France. 17. 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.
Abstract
CONTEXT: 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. PATIENTS AND 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. CONCLUSION: 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.
CONTEXT: 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. PATIENTS AND METHODS: We analysed a series of 55 index patients carrying the p.Ala541Thr variant. Their clinical profile was compared to that of 117 MEN1patients. 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 MEN1patients, but no p.Ala541Thrpatient had more than one cardinal MEN1 lesion at initial diagnosis. A second MEN1 lesion was diagnosed in 13% of MEN1patients 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. CONCLUSION: 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: Karen Rico; Suzann Duan; Ritu L Pandey; Yuliang Chen; Jayati T Chakrabarti; Julie Starr; Yana Zavros; Tobias Else; Bryson W Katona; David C Metz; Juanita L Merchant Journal: BMJ Open Gastroenterol Date: 2021-11