Specific missense mutations in NEMO result in hyper-IgM syndrome with hypohydrotic ectodermal dysplasia

Ashish Jain; Chi Adrian Ma; Shiyung Liu; Margaret Brown; Jeffrey Cohen; Warren Strober

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Specific missense mutations in NEMO result in hyper-IgM syndrome with hypohydrotic ectodermal dysplasia

机译：NEMO中的特定错义突变导致高IgM综合征并伴有水生性外胚层发育不良

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The gene that encodes nuclear factor κB (NF-κB) essential modulator (or NEMO, also known as IKKγ) is required for activation of the transcription factor NF-κB. We describe mutations in the putative zinc-finger domain of NEMO that result in an X-linked primary immunodeficiency characterized by hyper-IgM syndrome and hypohydrotic ectodermal dysplasia (XHM-ED). These mutations prevent CD40 ligand (CD40L)-mediated degradation of inhibitor of NF-κB α (IκB-α) and account for the following observations: B cells from XHM-ED patients are unable to undergo immunoglobulin class-switch recombination and antigen-presenting cells (APCs) are unable to synthesize the NF-κB-regulated cytokines interleukin 12 (IL-12) or tumor necrosis factor α(TNF-α) when stimulated with CD40L. nevertheless, innate immunity is preserved in XHM-ED patients because APCs retain the capacity to respond to stimulation by lipopolysaccharide or Staphylococcus aureus Cowan's antigen (SAC). Overall, the phenotype observed in XHM-ED patients shows that the putative zinc-finger domain of NEMO has a regulatory function and demonstrates the definite requirement of CD40-mediated NF-κB activation for B cell immunoglobulin class-switching.

机译：激活核转录因子NF-κB需要编码核因子κB（NF-κB）必需调节剂（或NEMO，也称为IKKγ）的基因。我们描述了NEMO的假定锌指结构域中的突变，该突变导致以X-连锁的主要免疫缺陷为特征的高IgM综合征和低水度外胚层发育不良（XHM-ED）。这些突变阻止了CD40配体（CD40L）介导的NF-κBα（IκB-α）抑制剂的降解，并解释了以下发现：XHM-ED患者的B细胞无法进行免疫球蛋白类别转换重组和抗原呈递CD40L刺激后，细胞（APC）无法合成NF-κB调节的细胞因子白介素12（IL-12）或肿瘤坏死因子α（TNF-α）。但是，由于APC保留了对脂多糖或金黄色葡萄球菌Cowan抗原（SAC）刺激的反应能力，因此XHM-ED患者保留了先天免疫力。总体而言，在XHM-ED患者中观察到的表型表明，NEMO的假定锌指结构域具有调节功能，并证明了CD40介导的NF-κB激活对于B细胞免疫球蛋白类别转换的明确要求。

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《Nature immunology》 |2001年第3期|共6页
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Ashish Jain; Chi Adrian Ma; Shiyung Liu; Margaret Brown; Jeffrey Cohen; Warren Strober;
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1. Specific missense mutations in NEMO result in hyper-IgM syndrome with hypohydrotic ectodermal dysplasia [J] . Ashish Jain, Chi Adrian Ma, Shiyung Liu, Nature immunology . 2001,第3期

机译：NEMO中的特定错义突变导致高IgM综合征并伴有水生性外胚层发育不良
2. Mutations in GRHL2 result in an autosomal-recessive ectodermal Dysplasia syndrome. [J] . Gabriela Petrof, Arti Nanda, Jake Howden, The American Journal of Human Genetics . 2014,第3期

机译：GRHL2中的突变导致常染色体隐性外胚层发育异常综合征。
3. Homozygous splice site mutations in PKP1 result in loss of epidermal plakophilin 1 expression and underlie ectodermal dysplasia/skin fragility syndrome in two consanguineous families. [J] . Sprecher E, Molho Pessach V, Ingber A, The Journal of investigative dermatology. . 2004,第3期

机译：PKP1中的纯合剪接位点突变导致表皮plakophilin 1表达丧失，并成为两个近亲家庭的表皮异型增生/皮肤脆性综合征的基础。
4. Phenotype Characterization And Candidate Genotyping Of Hypodontia In Ectodermal Dysplasia (ED) And Non-Syndromic Groups [D] . Olmsted, Matthew John 2011

机译：外胚层发育不良（ED）和非综合征人群的齿龈发育不足的表型表征和候选基因分型
5. Two-sided Ubiquitin Binding of NF-κB Essential Modulator (NEMO) Zinc Finger Unveiled by a Mutation Associated with Anhidrotic Ectodermal Dysplasia with Immunodeficiency Syndrome [O] . Flora Ngadjeua, Jeanne Chiaravalli, François Traincard, 2017

机译：双面泛素结合的NF-κB必需调节剂（NEMO）锌指与无免疫缺陷性表皮发育不良伴免疫缺陷综合征相关的突变揭开面纱。
6. Missense mutations in GJB2 encoding connexin-26 cause the ectodermal dysplasia Keratitis-Ichthyosis-Deafness syndrome. [O] . Willoughby, Colin, Russell, L., Uitto, J., 2002

机译：GJB2编码连接蛋白26的错义突变会导致外胚层发育异常角膜炎，鱼鳞病，耳聋综合征。

Specific missense mutations in NEMO result in hyper-IgM syndrome with hypohydrotic ectodermal dysplasia

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