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. mutations have recently been identified in patients with ACTH and variable immunodeficiency. A similar mutation was previously found in in the immunodeficient 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. mice were examined for endocrine developmental anomalies. Results: Mutations in the gene were identified in three of our families through whole exome sequencing, and in a fourth by direct Sanger sequencing. 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 NFKB2 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 in the remaining two probands; whole exome sequencing has been performed for one of these. mice, carrying a similar C-terminal mutation, showed normal pituitary anatomy and expression of proopiomelanocortin (POMC). Conclusions: We confirm previous indings that mutations near the C-terminus of cause combined endocrine and immunodeficiencies. 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 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 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.