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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.

Mutations in NFKB2and potential genetic heterogeneity in patients with DAVID syndrome, having variable endocrine and immune deficiencies