Mutations in NFKB2 and potential genetic heterogeneity in patients with DAVID syndrome, having variable endocrine and immune deficiencies.
Mutations in NFKB2 and potential genetic heterogeneity in patients with DAVID syndrome, having variable endocrine and immune deficiencies.
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DOI：
10.1186/s12881-014-0139-9
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发表时间：
2014-12-19
影响因子：
--
通讯作者：
Samuels ME
中科院分区：
文献类型：
--
作者：
Brue T;Quentien MH;Khetchoumian K;Bensa M;Capo-Chichi JM;Delemer B;Balsalobre A;Nassif C;Papadimitriou DT;Pagnier A;Hasselmann C;Patry L;Schwartzentruber J;Souchon PF;Takayasu S;Enjalbert A;Van Vliet G;Majewski J;Drouin J;Samuels ME
大卫综合征是一种罕见的垂体前叶激素缺乏症与常见的可变免疫缺陷相结合的疾病。最近在ACTH和可变免疫缺陷患者中发现了NFKB 2突变。以前在免疫缺陷的Nfkb 1小鼠品系中发现了类似的突变，但未评估突变对内分泌功能的影响。我们确定了6个不相关的大卫综合征家族。我们进行了整个外显子组和传统的桑格测序来寻找致病基因。检查了101只小鼠的内分泌发育异常。在我们的三个家庭中，通过全外显子组测序确定了NF KB 2基因的突变，在第四个家庭中通过直接桑格测序确定了NF KB 2基因的突变。在三个家族中可以证明突变的从头起源。所有突变都位于蛋白编码区的C-末端附近，靠近通过旁路途径加工NF-ΚB2蛋白所需的信号。两个先证者有解剖垂体异常，一个有生长和甲状腺激素以及ACTH缺乏症;这些发现以前没有报道过。其中一个先证者的两个孩子携带突变，迄今为止只表现出免疫表型。在其余两个先证者中，在NFKB 2的C-末端附近未发现突变;已对其中一个进行了全外显子组测序。携带类似Nfkb 2 C-末端突变的Nfkb 1小鼠显示正常的垂体解剖结构和前阿黑皮素（POMC）表达。我们证实了以前的研究结果，即NFKB 2的C-末端附近的突变会导致内分泌和免疫缺陷。在父母双方均可获得的所有病例中，均确认了突变的从头状态。这些突变与显性功能获得效应一致，产生未加工的NFKB 2超阻遏蛋白。我们扩大了这种NFKB 2突变的潜在表型，包括额外的垂体激素缺乏症以及解剖垂体异常。在DAVID 1小鼠中缺乏可观察到的内分泌表型表明，大卫综合征的内分泌成分不是由于NF κ B通路对垂体发育的直接作用，或者人和小鼠垂体发育对NF κ B通路功能的要求不同。本文的在线版本（doi：10.1186/s12881-014-0139-9）包含补充材料，可供授权用户使用。
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. 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. 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). 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. The online version of this article (doi:10.1186/s12881-014-0139-9) contains supplementary material, which is available to authorized users.
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影响因子：
3.9
作者：
Majewski, Jacek;Schwartzentruber, Jeremy A.;Samuels, Mark E.
通讯作者：
Samuels, Mark E.
影响因子：
3
作者：
Benoit, Genevieve;Lapeyraque, Anne-Laure;Haddad, Elie
通讯作者：
Haddad, Elie
影响因子：
3.5
作者：
Stoppa-Vaucher, S.;Ayabe, T.;Deal, C. L.
通讯作者：
Deal, C. L.
影响因子：
4.4
作者：
Tucker, Elena;O'Donnel, Kristy;Starr, Robyn
通讯作者：
Starr, Robyn
影响因子：
9.1
作者：
Liu, Yiwen;Hanson, Steven;Ibrahim, Mohammad A. A.
通讯作者：
Ibrahim, Mohammad A. A.