title: Mutations in NFKB2 and potential genetic heterogeneity in patients with DAVID syndrome, having variable endocrine and immune deficiencies.
abstract: BACKGROUND
  DAVID syndrome is a rare condition combining anterior pituitary hormone deficiency with common variable immunodeficiency. NFKB2 mutations have recently been identified in patients with ACTH and variable immunodeficiency. A similar mutation was previously found in Nfkb2 in the immunodeficient Lym1 mouse strain, but the effect of the mutation on endocrine function was not evaluated.
  
  
  METHODS
  We ascertained six unrelated DAVID syndrome families. We performed whole exome and traditional Sanger sequencing to search for causal genes. Lym1 mice were examined for endocrine developmental anomalies.
  
  
  RESULTS
  Mutations in the NFKB2 gene were identified in three of our families through whole exome sequencing, and in a fourth by direct Sanger sequencing. De novo origin of the mutations could be demonstrated in three of the families. All mutations lie near the C-terminus of the protein-coding region, near signals required for processing of NFΚB2 protein by the alternative pathway. Two of the probands had anatomical pituitary anomalies, and one had growth and thyroid hormone as well as ACTH deficiency; these findings have not been previously reported. Two children of one of the probands carried the mutation and have to date exhibited only an immune phenotype. No mutations were found near the C-terminus of NFKB2 in the remaining two probands; whole exome sequencing has been performed for one of these. Lym1 mice, carrying a similar Nfkb2 C-terminal mutation, showed normal pituitary anatomy and expression of proopiomelanocortin (POMC).
  
  
  CONCLUSIONS
  We confirm previous findings that mutations near the C-terminus of NFKB2 cause combined endocrine and immunodeficiencies. De novo status of the mutations was confirmed in all cases for which both parents were available. The mutations are consistent with a dominant gain-of-function effect, generating an unprocessed NFKB2 super-repressor protein. We expand the potential phenotype of such NFKB2 mutations to include additional pituitary hormone deficiencies as well as anatomical pituitary anomalies. The lack of an observable endocrine phenotype in Lym1 mice suggests that the endocrine component of DAVID syndrome is either not due to a direct role of NFKB pathways on pituitary development, or else that human and mouse pituitary development differ in its requirements for NFKB pathway function.
authors.affiliation: Aix-Marseille University, Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille (CRN2M), Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7286, Faculté de Médecine de Marseille, 13344, Marseille, France. Thierry.BRUE@ap-hm.fr.|Assistance Publique-Hôpitaux de Marseille (APHM), Department of Endocrinology, Centre de Référence des Maladies Rares d'Origine Hypophysaire, Hôpital de la Timone, 13005, Marseille, France. Thierry.BRUE@ap-hm.fr.
authors.forename: Thierry
authors.initials: T
authors.lastname: Brue
authors.affiliation: Aix-Marseille University, Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille (CRN2M), Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7286, Faculté de Médecine de Marseille, 13344, Marseille, France. marie-helene.quentien@univ-amu.fr.|Assistance Publique-Hôpitaux de Marseille (APHM), Department of Endocrinology, Centre de Référence des Maladies Rares d'Origine Hypophysaire, Hôpital de la Timone, 13005, Marseille, France. marie-helene.quentien@univ-amu.fr.
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Quentien
authors.affiliation: Laboratoire de Génétique moléculaire, Institut de recherches cliniques de Montréal, 110 Avenue des Pins Ouest, Montréal, QC, H2W 1R7, Canada. Konstantin.Khetchoumian@ircm.qc.ca.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Khetchoumian
authors.affiliation: Ospedale Bufalini, Department of Paediatrics, Cesena, FC, Italy. mbensa@ausl-cesena.emr.it.
authors.forename: Marco
authors.initials: M
authors.lastname: Bensa
authors.affiliation: Centre de Recherche du CHU Ste-Justine, 3175 Cote Ste-Catherine, Montreal, QC, Canada. jose.capo-chichi@umontreal.ca.
authors.forename: José-Mario
authors.initials: JM
authors.lastname: Capo-Chichi
authors.affiliation: Departments of Endocrinology and of Pediatrics, Centre Hospitalier Robert Debré, 51092, Reims, France. bdelemer@chu-reims.fr.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Delemer
authors.affiliation: Laboratoire de Génétique moléculaire, Institut de recherches cliniques de Montréal, 110 Avenue des Pins Ouest, Montréal, QC, H2W 1R7, Canada. aurelio.balsalobre@ircm.qc.ca.
authors.forename: Aurelio
authors.initials: A
authors.lastname: Balsalobre
authors.affiliation: Centre de Recherche du CHU Ste-Justine, 3175 Cote Ste-Catherine, Montreal, QC, Canada. christina.nassif@recherche-ste-justine.qc.ca.
authors.forename: Christina
authors.initials: C
authors.lastname: Nassif
authors.affiliation: Department of Pediatric-Adolescent Endocrinology and Diabetes, Athens Medical Center, Athens, Greece. DTPapadimitriou@in.gr.
authors.forename: Dimitris T
authors.initials: DT
authors.lastname: Papadimitriou
authors.affiliation: Clinique universitaire de pédiatrie, CHU de Grenoble, Grenoble, France. APagnier@chu-grenoble.fr.
authors.forename: Anne
authors.initials: A
authors.lastname: Pagnier
authors.affiliation: Centre de Recherche du CHU Ste-Justine, 3175 Cote Ste-Catherine, Montreal, QC, Canada. chasselmann@mac.com.
authors.forename: Caroline
authors.initials: C
authors.lastname: Hasselmann
authors.affiliation: Centre de Recherche du CHU Ste-Justine, 3175 Cote Ste-Catherine, Montreal, QC, Canada. lyspatry@hotmail.com.
authors.forename: Lysanne
authors.initials: L
authors.lastname: Patry
authors.affiliation: Department of Human Genetics, McGill University, Montreal, QC, Canada. jeremy37@gmail.com.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Schwartzentruber
authors.affiliation: Departments of Endocrinology and of Pediatrics, Centre Hospitalier Robert Debré, 51092, Reims, France. pfsouchon@chu-reims.fr.
authors.forename: Pierre-François
authors.initials: PF
authors.lastname: Souchon
authors.affiliation: Laboratoire de Génétique moléculaire, Institut de recherches cliniques de Montréal, 110 Avenue des Pins Ouest, Montréal, QC, H2W 1R7, Canada. Shinobu.Takayasu@ircm.qc.ca.
authors.forename: Shinobu
authors.initials: S
authors.lastname: Takayasu
authors.affiliation: Aix-Marseille University, Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille (CRN2M), Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7286, Faculté de Médecine de Marseille, 13344, Marseille, France. alain.enjalbert@univ-amu.fr.|Assistance Publique-Hôpitaux de Marseille (APHM), Department of Endocrinology, Centre de Référence des Maladies Rares d'Origine Hypophysaire, Hôpital de la Timone, 13005, Marseille, France. alain.enjalbert@univ-amu.fr.
authors.forename: Alain
authors.initials: A
authors.lastname: Enjalbert
authors.affiliation: Endocrinology Service and Research Center, Department of Pediatrics, CHU Ste-Justine, University of Montreal, Montreal, QC, Canada. guy.van-vliet@recherche-ste-justine.qc.ca.
authors.forename: Guy
authors.initials: G
authors.lastname: Van Vliet
authors.affiliation: Department of Human Genetics, McGill University, Montreal, QC, Canada. jacek.majewski@mcgill.ca.
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.affiliation: Laboratoire de Génétique moléculaire, Institut de recherches cliniques de Montréal, 110 Avenue des Pins Ouest, Montréal, QC, H2W 1R7, Canada. Jacques.Drouin@ircm.qc.ca.
authors.forename: Jacques
authors.initials: J
authors.lastname: Drouin
authors.affiliation: Centre de Recherche du CHU Ste-Justine, 3175 Cote Ste-Catherine, Montreal, QC, Canada. mark.e.samuels@umontreal.ca.|Department of Medicine, University of Montreal, Montreal, QC, Canada. mark.e.samuels@umontreal.ca.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Samuels
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D018740:Genetic Heterogeneity; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D009154:Mutation; D052003:NF-kappa B p52 Subunit / Q000235:genetics*; D010375:Pedigree; D010908:Pituitary Hormones, Anterior / Q000172:deficiency*; D011333:Pro-Opiomelanocortin
chemical_list: D052003:NF-kappa B p52 Subunit; C498206:NFKB2 protein, human; C498207:Nfkb2 protein, mouse; D010908:Pituitary Hormones, Anterior; D011333:Pro-Opiomelanocortin