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BMC Med Genet. 2014 Dec 19;15:139. doi: 10.1186/s12881-014-0139-9.

Mutations in NFKB2 and potential genetic heterogeneity in patients with DAVID syndrome, having variable endocrine and immune deficiencies.

Author information

  • 1Aix-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.
  • 2Assistance 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.
  • 3Aix-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.
  • 4Assistance 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.
  • 5Laboratoire de Génétique moléculaire, Institut de recherches cliniques de Montréal, 110 Avenue des Pins Ouest, Montréal, QC, H2W 1R7, Canada. Konstantin.Khetchoumian@ircm.qc.ca.
  • 6Ospedale Bufalini, Department of Paediatrics, Cesena, FC, Italy. mbensa@ausl-cesena.emr.it.
  • 7Centre de Recherche du CHU Ste-Justine, 3175 Cote Ste-Catherine, Montreal, QC, Canada. jose.capo-chichi@umontreal.ca.
  • 8Departments of Endocrinology and of Pediatrics, Centre Hospitalier Robert Debré, 51092, Reims, France. bdelemer@chu-reims.fr.
  • 9Laboratoire de Génétique moléculaire, Institut de recherches cliniques de Montréal, 110 Avenue des Pins Ouest, Montréal, QC, H2W 1R7, Canada. aurelio.balsalobre@ircm.qc.ca.
  • 10Centre de Recherche du CHU Ste-Justine, 3175 Cote Ste-Catherine, Montreal, QC, Canada. christina.nassif@recherche-ste-justine.qc.ca.
  • 11Department of Pediatric-Adolescent Endocrinology and Diabetes, Athens Medical Center, Athens, Greece. DTPapadimitriou@in.gr.
  • 12Clinique universitaire de pédiatrie, CHU de Grenoble, Grenoble, France. APagnier@chu-grenoble.fr.
  • 13Centre de Recherche du CHU Ste-Justine, 3175 Cote Ste-Catherine, Montreal, QC, Canada. chasselmann@mac.com.
  • 14Centre de Recherche du CHU Ste-Justine, 3175 Cote Ste-Catherine, Montreal, QC, Canada. lyspatry@hotmail.com.
  • 15Department of Human Genetics, McGill University, Montreal, QC, Canada. jeremy37@gmail.com.
  • 16Departments of Endocrinology and of Pediatrics, Centre Hospitalier Robert Debré, 51092, Reims, France. pfsouchon@chu-reims.fr.
  • 17Laboratoire de Génétique moléculaire, Institut de recherches cliniques de Montréal, 110 Avenue des Pins Ouest, Montréal, QC, H2W 1R7, Canada. Shinobu.Takayasu@ircm.qc.ca.
  • 18Aix-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.
  • 19Assistance 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.
  • 20Endocrinology Service and Research Center, Department of Pediatrics, CHU Ste-Justine, University of Montreal, Montreal, QC, Canada. guy.van-vliet@recherche-ste-justine.qc.ca.
  • 21Department of Human Genetics, McGill University, Montreal, QC, Canada. jacek.majewski@mcgill.ca.
  • 22Laboratoire de Génétique moléculaire, Institut de recherches cliniques de Montréal, 110 Avenue des Pins Ouest, Montréal, QC, H2W 1R7, Canada. Jacques.Drouin@ircm.qc.ca.
  • 23Centre de Recherche du CHU Ste-Justine, 3175 Cote Ste-Catherine, Montreal, QC, Canada. mark.e.samuels@umontreal.ca.
  • 24Department of Medicine, University of Montreal, Montreal, QC, Canada. mark.e.samuels@umontreal.ca.

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.

PMID:
25524009
[PubMed - indexed for MEDLINE]
PMCID:
PMC4411703
Free PMC Article
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