Ozlem Okutman1,2,3, Jean Muller4,5, Valerie Skory1, Jean Marie Garnier6, Angeline Gaucherot7, Yoni Baert8, Valérie Lamour9, Munevver Serdarogullari10, Meral Gultomruk10, Albrecht Röpke11, Sabine Kliesch12, Viviana Herbepin13, Isabelle Aknin14, Moncef Benkhalifa15, Marius Teletin1, Emre Bakircioglu16, Ellen Goossens8, Nicolas Charlet-Berguerand7, Mustafa Bahceci10, Frank Tüttelmann11, STéphane Viville17,18,19,20. 1. Département Génomique Fonctionnelle et Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de Santé et de Recherche Médicale (INSERM) U964/Centre National de Recherche Scientifique (CNRS) UMR 7104, Université de Strasbourg, 67404, Illkirch, France. 2. Institut de Parasitologie et Pathologie Tropicale, EA 7292, Fédération de Médecine Translationelle, Université de Strasbourg, 3 rue Koeberlé, 67000, Strasbourg, France. 3. Laboratoire de Diagnostic Génétique, UF3472-génétique de l'infertilité, Hôpitaux Universitaires de Strasbourg, 67000, Strasbourg, France. 4. Laboratoire de Diagnostic Génétique, Hôpitaux Universitaires de Strasbourg, Strasbourg, France. 5. Laboratoire de Génétique Médicale, INSERM U1112, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France. 6. Biologie du développement et cellules souches, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de Santé et de Recherche Médicale (INSERM) U964/Centre National de Recherche Scientifique (CNRS) UMR 7104, Université de Strasbourg, 67404, Illkirch, France. 7. Médecine translationnelle et neurogénétique, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de Santé et de Recherche Médicale (INSERM) U964/Centre National de Recherche Scientifique (CNRS) UMR 7104, Université de Strasbourg, 67404, Illkirch, France. 8. Biology of the Testis, Research Laboratory for Reproduction, Genetics and Regenerative Medicine, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090, Brussels, Belgium. 9. Département Biologie structurale intégrative, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de Santé et de Recherche Médicale (INSERM) U964/Centre National de Recherche Scientifique (CNRS) UMR 7104, Université de Strasbourg, 67404, Illkirch, France. 10. Bahceci Health Group, Sisli, 34365, Istanbul, Turkey. 11. Institute of Human Genetics, University of Münster, Münster, Germany. 12. Centre of Reproductive Medicine and Andrology, University of Münster, Münster, Germany. 13. Genetics Department, CHU-Hôpital Nord, Saint-Etienne, France. 14. Reproductive Biology Unit, CHU-Hôpital Nord, Saint-Etienne, France. 15. Médecine de la Reproduction et Cytogénétique Médicale CHU et Faculté de Médecine, Université de Picardie Jules Verne, 80000, Amiens, France. 16. Unimed Center, Sisli, 34365, Istanbul, Turkey. 17. Département Génomique Fonctionnelle et Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de Santé et de Recherche Médicale (INSERM) U964/Centre National de Recherche Scientifique (CNRS) UMR 7104, Université de Strasbourg, 67404, Illkirch, France. stephane.viville@unistra.fr. 18. Institut de Parasitologie et Pathologie Tropicale, EA 7292, Fédération de Médecine Translationelle, Université de Strasbourg, 3 rue Koeberlé, 67000, Strasbourg, France. stephane.viville@unistra.fr. 19. Laboratoire de Diagnostic Génétique, UF3472-génétique de l'infertilité, Hôpitaux Universitaires de Strasbourg, 67000, Strasbourg, France. stephane.viville@unistra.fr. 20. Laboratoire de diagnostic génétique, UF3472-génétique de l'infertilité, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, 1 place de l'Hôpital, 67091, Strasbourg cedex, France. stephane.viville@unistra.fr.
Abstract
PURPOSE: The purpose of this study was to identify mutations that cause non-syndromic male infertility using whole exome sequencing of family cases. METHODS: We recruited a consanguineous Turkish family comprising nine siblings with male triplets; two of the triplets were infertile as well as one younger infertile brother. Whole exome sequencing (WES) performed on two azoospermic brothers identified a mutation in the melanoma antigen family B4 (MAGEB4) gene which was confirmed via Sanger sequencing and then screened for on control groups and unrelated infertile subjects. The effect of the mutation on messenger RNA (mRNA) and protein levels was tested after in vitro cell transfection. Structural features of MAGEB4 were predicted throughout the conserved MAGE domain. RESULTS: The novel single-base substitution (c.1041A>T) in the X-linked MAGEB4 gene was identified as a no-stop mutation. The mutation is predicted to add 24 amino acids to the C-terminus of MAGEB4. Our functional studies were unable to detect any effect either on mRNA stability, intracellular localization of the protein, or the ability to homodimerize/heterodimerize with other MAGE proteins. We thus hypothesize that these additional amino acids may affect the proper protein interactions with MAGEB4 partners. CONCLUSION: The whole exome analysis of a consanguineous Turkish family revealed MAGEB4 as a possible new X-linked cause of inherited male infertility. This study provides the first clue to the physiological function of a MAGE protein.
PURPOSE: The purpose of this study was to identify mutations that cause non-syndromic male infertility using whole exome sequencing of family cases. METHODS: We recruited a consanguineous Turkish family comprising nine siblings with male triplets; two of the triplets were infertile as well as one younger infertile brother. Whole exome sequencing (WES) performed on two azoospermic brothers identified a mutation in the melanoma antigen family B4 (MAGEB4) gene which was confirmed via Sanger sequencing and then screened for on control groups and unrelated infertile subjects. The effect of the mutation on messenger RNA (mRNA) and protein levels was tested after in vitro cell transfection. Structural features of MAGEB4 were predicted throughout the conserved MAGE domain. RESULTS: The novel single-base substitution (c.1041A>T) in the X-linked MAGEB4 gene was identified as a no-stop mutation. The mutation is predicted to add 24 amino acids to the C-terminus of MAGEB4. Our functional studies were unable to detect any effect either on mRNA stability, intracellular localization of the protein, or the ability to homodimerize/heterodimerize with other MAGE proteins. We thus hypothesize that these additional amino acids may affect the proper protein interactions with MAGEB4 partners. CONCLUSION: The whole exome analysis of a consanguineous Turkish family revealed MAGEB4 as a possible new X-linked cause of inherited male infertility. This study provides the first clue to the physiological function of a MAGE protein.
Authors: Liesbeth Visser; G Henrike Westerveld; Fang Xie; Saskia K M van Daalen; Fulco van der Veen; M Paola Lombardi; Sjoerd Repping Journal: Fertil Steril Date: 2011-01-21 Impact factor: 7.329
Authors: Peter D Stenson; Matthew Mort; Edward V Ball; Katy Howells; Andrew D Phillips; Nick St Thomas; David N Cooper Journal: Genome Med Date: 2009-01-22 Impact factor: 11.117
Authors: Laura Kasak; Margus Punab; Liina Nagirnaja; Marina Grigorova; Ave Minajeva; Alexandra M Lopes; Anna Maria Punab; Kenneth I Aston; Filipa Carvalho; Eve Laasik; Lee B Smith; Donald F Conrad; Maris Laan Journal: Am J Hum Genet Date: 2018-08-02 Impact factor: 11.025
Authors: Klementina Fon Tacer; Marhiah C Montoya; Melissa J Oatley; Tessa Lord; Jon M Oatley; Jonathon Klein; Ramya Ravichandran; Heather Tillman; MinSoo Kim; Jon P Connelly; Shondra M Pruett-Miller; Angie L Bookout; Emily Binshtock; Marcin M Kamiński; Patrick Ryan Potts Journal: Sci Adv Date: 2019-05-29 Impact factor: 14.136
Authors: Amal Robay; Saleha Abbasi; Ammira Akil; Haitham El-Bardisi; Mohamed Arafa; Ronald G Crystal; Khalid A Fakhro Journal: Arab J Urol Date: 2018-02-14