title: A no-stop mutation in MAGEB4 is a possible cause of rare X-linked azoospermia and oligozoospermia in a consanguineous Turkish family.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.affiliation: 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.|Institut de Parasitologie et Pathologie Tropicale, EA 7292, Fédération de Médecine Translationelle, Université de Strasbourg, 3 rue Koeberlé, 67000, Strasbourg, France.|Laboratoire de Diagnostic Génétique, UF3472-génétique de l'infertilité, Hôpitaux Universitaires de Strasbourg, 67000, Strasbourg, France.
authors.forename: Ozlem
authors.initials: O
authors.lastname: Okutman
authors.affiliation: Laboratoire de Diagnostic Génétique, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.|Laboratoire de Génétique Médicale, INSERM U1112, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Muller
authors.affiliation: 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.
authors.forename: Valerie
authors.initials: V
authors.lastname: Skory
authors.affiliation: 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.
authors.forename: Jean Marie
authors.initials: JM
authors.lastname: Garnier
authors.affiliation: 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.
authors.forename: Angeline
authors.initials: A
authors.lastname: Gaucherot
authors.affiliation: Biology of the Testis, Research Laboratory for Reproduction, Genetics and Regenerative Medicine, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090, Brussels, Belgium.
authors.forename: Yoni
authors.initials: Y
authors.lastname: Baert
authors.affiliation: 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.
authors.forename: Valérie
authors.initials: V
authors.lastname: Lamour
authors.affiliation: Bahceci Health Group, Sisli, 34365, Istanbul, Turkey.
authors.forename: Munevver
authors.initials: M
authors.lastname: Serdarogullari
authors.affiliation: Bahceci Health Group, Sisli, 34365, Istanbul, Turkey.
authors.forename: Meral
authors.initials: M
authors.lastname: Gultomruk
authors.affiliation: Institute of Human Genetics, University of Münster, Münster, Germany.
authors.forename: Albrecht
authors.initials: A
authors.lastname: Röpke
authors.affiliation: Centre of Reproductive Medicine and Andrology, University of Münster, Münster, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Kliesch
authors.affiliation: Genetics Department, CHU-Hôpital Nord, Saint-Etienne, France.
authors.forename: Viviana
authors.initials: V
authors.lastname: Herbepin
authors.affiliation: Reproductive Biology Unit, CHU-Hôpital Nord, Saint-Etienne, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Aknin
authors.affiliation: Médecine de la Reproduction et Cytogénétique Médicale CHU et Faculté de Médecine, Université de Picardie Jules Verne, 80000, Amiens, France.
authors.forename: Moncef
authors.initials: M
authors.lastname: Benkhalifa
authors.affiliation: 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.
authors.forename: Marius
authors.initials: M
authors.lastname: Teletin
authors.affiliation: Unimed Center, Sisli, 34365, Istanbul, Turkey.
authors.forename: Emre
authors.initials: E
authors.lastname: Bakircioglu
authors.affiliation: Biology of the Testis, Research Laboratory for Reproduction, Genetics and Regenerative Medicine, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090, Brussels, Belgium.
authors.forename: Ellen
authors.initials: E
authors.lastname: Goossens
authors.affiliation: 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.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Charlet-Berguerand
authors.affiliation: Bahceci Health Group, Sisli, 34365, Istanbul, Turkey.
authors.forename: Mustafa
authors.initials: M
authors.lastname: Bahceci
authors.affiliation: Institute of Human Genetics, University of Münster, Münster, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Tüttelmann
authors.affiliation: 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.|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.|Laboratoire de Diagnostic Génétique, UF3472-génétique de l'infertilité, Hôpitaux Universitaires de Strasbourg, 67000, Strasbourg, France. stephane.viville@unistra.fr.|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.
authors.forename: STéphane
authors.initials: S
authors.lastname: Viville
mesh_terms: D000328:Adult; D000951:Antigens, Neoplasm / Q000235:genetics*; D053713:Azoospermia / Q000235:genetics* / Q000473:pathology; D002675:Child, Preschool; D003241:Consanguinity; D005787:Gene Frequency; D050172:Genes, X-Linked / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007248:Infertility, Male / Q000235:genetics* / Q000473:pathology; D008297:Male; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D009845:Oligospermia / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000235:genetics; D000073359:Exome Sequencing
chemical_list: D000951:Antigens, Neoplasm; C000626007:MAGEB4 protein, human; D009363:Neoplasm Proteins; D012333:RNA, Messenger
keywords: Azoospermia; MAGEB4; Male infertility; No-stop mutations; Oligozoospermia; Whole exome sequencing