Mutations in NFKB2 and potential genetic heterogeneity in patients with DAVID syndrome, having variable endocrine and immune deficiencies
| العنوان: | Mutations in NFKB2 and potential genetic heterogeneity in patients with DAVID syndrome, having variable endocrine and immune deficiencies |
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| المؤلفون: | Jacek Majewski, Caroline Hasselmann, Brigitte Delemer, Thierry Brue, Aurelio Balsalobre, Jose-Mario Capo-Chichi, Jeremy Schwartzentruber, Dimitris T. Papadimitriou, Marco Bensa, Marie-Helene Quentien, Lysanne Patry, Mark E. Samuels, Pierre-François Souchon, Konstantin Khetchoumian, Christina Nassif, Jacques Drouin, Shinobu Takayasu, Alain Enjalbert, Anne Pagnier, Guy Van Vliet |
| المساهمون: | Centre de recherche en neurobiologie - neurophysiologie de Marseille (CRN2M), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'Endocrinologie - Diabète - Nutrition [Reims], Université de Reims Champagne-Ardenne (URCA)-Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims), Alcatel-Lucent Bell - Belgique, Alacatel Lucent, McGill University and Genome Quebec Innovation Centre, CHU Sainte Justine [Montréal], Laboratory of Molecular Genetics, Institut de recherches cliniques de Montréal, Dumonceaud, Corinne |
| المصدر: | BMC Medical Genetics BMC Medical Genetics, 2014, 15, pp.139 BMC Medical Genetics, BioMed Central, 2014, 15, pp.139 |
| بيانات النشر: | HAL CCSD, 2014. |
| سنة النشر: | 2014 |
| مصطلحات موضوعية: | Male, Pro-Opiomelanocortin, medicine.disease_cause, MESH: NF-kappa B p52 Subunit, Mice, 0302 clinical medicine, MESH: Pro-Opiomelanocortin, Genetics(clinical), MESH: Animals, Exome, [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Genetics (clinical), Exome sequencing, Immunodeficiency, Sanger sequencing, Genetics, 0303 health sciences, Mutation, MESH: Genetic Heterogeneity, Phenotype, 3. Good health, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Pedigree, MESH: Pituitary Hormones, Anterior, 030220 oncology & carcinogenesis, symbols, Female, Research Article, MESH: Mutation, MESH: Immunologic Deficiency Syndromes, MESH: Pedigree, Biology, 03 medical and health sciences, symbols.namesake, Genetic Heterogeneity, NF-kappa B p52 Subunit, Pituitary Hormones, Anterior, medicine, Endocrine system, Animals, Humans, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], MESH: Mice, 030304 developmental biology, MESH: Humans, Genetic heterogeneity, Immunologic Deficiency Syndromes, medicine.disease, MESH: Male, Disease Models, Animal, MESH: Disease Models, Animal, MESH: Female |
| الوصف: | 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. Electronic supplementary material The online version of this article (doi:10.1186/s12881-014-0139-9) contains supplementary material, which is available to authorized users. |
| اللغة: | English |
| تدمد: | 1471-2350 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::fc823e72da80e35434173a3d4c13f7d2Test https://hal.science/hal-01176935Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....fc823e72da80e35434173a3d4c13f7d2 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14712350 |
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