A novel X-linked disorder of immune deficiency and hypohidrotic ectodermal dysplasia is allelic to incontinentia pigmenti and due to mutations in IKK-gamma (NEMO)
A novel X-linked disorder of immune deficiency and hypohidrotic ectodermal dysplasia is allelic to incontinentia pigmenti and due to mutations in IKK-gamma (NEMO)
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DOI：
10.1086/316914
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发表时间：
2000-12-01
影响因子：
9.8
通讯作者：
Ferguson, BM
中科院分区：
文献类型：
--
作者：
Zonana, J;Elder, ME;Ferguson, BM
少汗性外胚层发育不良(HED)是一种牙齿、头发和汗腺的先天性疾病，通常作为一种X连锁隐性性状遗传，尽管存在较罕见的常染色体显性和隐性形式。我们研究了来自四个患有HED和免疫缺陷(HED-ID)的家庭的男性，在这些家庭中，这种疾病被分离为X连锁的隐性性状。受影响的男性表现为丙种球蛋白异常血症，尽管接受了治疗，但因反复感染而有显著的发病率和死亡率。最近，IKK-Gamma(NEMO)基因突变被证明会导致家族性色素性失禁(LP)。与Hed-ID不同，IP影响女性，除极少数例外外，还会导致男性产前死亡。WT-γ是激活被称为核因子kappaB的转录因子所必需的，并在T和B细胞功能中发挥重要作用。我们推测，该基因的“较轻微”突变可能导致Hed-ID。在所有四个家族中，序列分析显示外显子10突变影响IKK-伽马蛋白的羧基末端，该区域被认为连接IKK信号复合体和上游激活物。这一发现定义了一种新的X连锁隐性免疫缺陷综合征，与其他类型的HED和免疫缺陷综合征不同。这些数据进一步证明，外胚层附属物的发育是通过肿瘤坏死因子/肿瘤坏死因子受体样信号通路介导的，其中IKK信号复合体起着重要作用。
Hypohidrotic ectodermal dysplasia (HED), a congenital disorder of teeth, hair, and eccrine sweat glands, is usually inherited as an X-linked recessive trait, although rarer autosomal dominant and recessive forms exist. We have studied males from four families with HED and immunodeficiency (HED-ID), in which the disorder segregates as an X-linked recessive trait. Affected males manifest dysgammaglobulinemia and, despite therapy, have significant morbidity and mortality from recurrent infections. Recently, mutations in IKK-gamma (NEMO) have been shown to cause familial incontinentia pigmenti (LP). Unlike HED-ID, IP affects females and, with few exceptions, causes male prenatal lethality. Wt-gamma is required for the activation of the transcription factor known as "nuclear factor kappa B" and plays an important role in T and B cell function. We hypothesize that "milder" mutations at this locus may cause HED-ID. In all four families, sequence analysis reveals exon 10 mutations affecting the carboxy-terminal end of the IKK-gamma protein, a domain believed to connect the IKK signalsome complex to upstream activators. The findings define a new X-linked recessive immunodeficiency syndrome, distinct from other types of HED and immunodeficiency syndromes. The data provide further evidence that the development of ectodermal appendages is mediated through a tumor necrosis factor/tumor necrosis factor receptor-like signaling pathway, with the IKK signalsome complex playing a significant role.