Congenital alterations of NEMO glutamic acid 223 result in hypohidrotic ectodermal dysplasia and immunodeficiency with normal serum IgG levels.
Congenital alterations of NEMO glutamic acid 223 result in hypohidrotic ectodermal dysplasia and immunodeficiency with normal serum IgG levels.
复制标题
NEMO 谷氨酸 223 的先天性改变会导致少汗性外胚层发育不良和血清 IgG 水平正常的免疫缺陷。
DOI：
10.1016/j.anai.2011.03.009
复制
发表时间：
2011
期刊：
影响因子：
--
通讯作者：
Orange,JordanS
中科院分区：
文献类型：
--
作者：
Karamchandani-Patel,Gital;Hanson,EricP;Saltzman,Rushani;Kimball,CEve;Sorensen,RicardoU;Orange,JordanS
背景NF-κB必需调节因子（NEMO）基因的亚型突变导致多种躯体和免疫异常综合征。临床相关的基因型-表型协会是必不可少的了解这种复杂的疾病。目的研究2例NEMO基因第223位密码子突变的无血缘关系男孩的表型相似性，以探讨基因型与表型的关系。方法对患者的临床和实验室指标进行评价，包括细胞计数、免疫球蛋白的数量和质量、NK细胞杀伤活性、Toll样和TNF受体信号传导。由于这两种突变均影响NEMO密码子223，并且是新的，因此考虑了新的潜在基因型-表型关联。结果两例患者均为少水型外胚叶发育不良，并有严重或反复感染。1例为反复鼻窦炎感染，另1例为坏死性软组织MRSA感染和咽峡炎链球菌硬膜下脓胸伴菌血症。NEMO基因序列显示一个三核苷酸缺失（c.667_669delGAG）在一个病人和一个替代（667 G>A）在另一个。这些分别预测NEMO谷氨酸223的缺失或其被赖氨酸取代。两例患者的血清IgG水平正常，但特异性抗体较差。NK细胞毒性、Toll样和TNF受体信号传导也受损。免疫球蛋白替代治疗后，两例患者均未发生严重细菌感染。结论影响NEMO谷氨酸223的两种不同的新突变导致临床相关的相似表型，为支持该疾病的基因型-表型相关性提供了进一步的证据。他们认为NEMO残基223是外胚层发育和免疫所必需的，并且显然是定量IgG产生所必需的，但可能是特异性抗体产生所必需的。
Background Hypomorphic mutations in the NF-κB essential modulator (NEMO) gene result in a variable syndrome of somatic and immunological abnormalities. Clinically relevant genotype-phenotype associations are essential to understanding this complex disease. Objective Two unrelated boys with novel NEMO mutations altering codon 223 were studied for similarity in phenotype in consideration of potential genotype-phenotype associations. Methods Clinical and Laboratory features including cell counts, immunoglobulin quantity and quality, NK cell cytotoxicity, Toll-like and TNF receptor signaling were evaluated. Since both mutations affected NEMO codon 223 and were novel, consideration was given to new potential genotype-phenotype associations. Results Both patients were diagnosed with hypohydrotic ectodermal dysplasia and had severe or recurrent infections. One had recurrent sinopulmonary infections and the other necrotizing soft tissue MRSA infection and Streptococcus anginosus subdural empyema with bacteremia. NEMO gene sequence demonstrated a three-nucleotide deletion (c.667_669delGAG) in one patient and a substitution (667G>A) in the other. These predict either the deletion of NEMO glutamic acid 223 or it being replaced with lysine, respectively. Both patients had normal serum IgG levels but poor specific antibodies. NK cell cytotoxicity, Toll-like and TNF receptor signaling was also impaired. Serious bacterial infection did not occur in both patients after immunoglobulin replacement therapy. Conclusions Two different novel mutations affecting NEMO glutamic acid 223 resulted in clinically relevant similar phenotypes providing further evidence to support genotype-phenotype correlations in this disease. They suggest NEMO residue 223 is required for ectodermal development and immunity and is apparently dispensable for quantitative IgG production, but may be required for specific antibody production.