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. 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

Thierry Brue  1   2 , Marie-Hélène Quentien  3   4 , Konstantin Khetchoumian  5 , Marco Bensa  6 , José-Mario Capo-Chichi  7 , Brigitte Delemer  8 , Aurelio Balsalobre  9 , Christina Nassif  10 , Dimitris T Papadimitriou  11 , Anne Pagnier  12 , Caroline Hasselmann  13 , Lysanne Patry  14 , Jeremy Schwartzentruber  15 , Pierre-François Souchon  16 , Shinobu Takayasu  17 , Alain Enjalbert  18   19 , Guy Van Vliet  20 , Jacek Majewski  21 , Jacques Drouin  22 , Mark E Samuels  23   24
Affiliations

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

Thierry Brue et al. BMC Med Genet. .

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.

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Figures

Figure 1
Figure 1
DAVID syndrome families and NFKB2 gene structure with mutations. A-D, pedigrees showing genotypes of sequenced individuals. Symbols: Filled, immunodeficiency, ACTH deficiency, GH deficiency; lower half filled, immunodeficiency; lower half plus upper left quadrant filled, immunodeficiency, ACTH deficiency; open, unaffected or unknown. n.a. DNA and clinical information not available. +/+, no mutation at any of the three sites found in the families. E, structure of the NFκB2 protein (isoform A numbering), indicating the major functional domains, regulated phosphorylated serines 866 and 870, and sites of mutations reported here, by Chen, Liu, Lee, Lindsley et al, or at the orthologous site in the Lym1 mouse (Tucker et al). The vertical arrow above the domain cartoon indicates approximate site of proteolytic cleavage of p100, which releases the amino-terminal p52 active fragment. RHD, rel homology domain; ARDs, ankyrin repeat domains; DD, death domain; NRD, NIK response domain.
Figure 2
Figure 2
Histology of Lym1 mutant mouse pituitaries and adrenals. HE staining of pituitaries (A, E, I) and adrenals (D, H, L) from WT (A, D), heterozygous (Nfkb2 Lym1/+) or homozygous (Nfkb2 Lym1/Lym1) newborn mice. Staining of pituitaries with anti-ACTH (B, F, J) or anti-Tpit (C, G, K) antibodies in wild type, heterozygous, and homozygous mutant mice respectively. AL: anterior lobe, IL: intermediate lobe, PL: posterior lobe. Scale bars are shown.
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