Inherited p40phox deficiency differs from classic chronic granulomatous disease
Inherited p40phox deficiency differs from classic chronic granulomatous disease
复制标题
DOI：
10.1172/jci97116
复制
发表时间：
2018-08-31
影响因子：
15.9
通讯作者：
Bustamante, Jacinta
中科院分区：
文献类型：
--
作者：
van de Geer, Annemarie;Nieto-Patlan, Alejandro;Bustamante, Jacinta
仅在1例患者中描述了编码吞噬细胞NADPH氧化酶p40（phox）亚基的NCF 4基因的双等位基因功能丧失（LOF）突变。我们报告24 p40（phox）缺乏症患者从12个家庭在8个国家。这些患者显示出8种不同的NCF 4框内或框外突变，这些突变在11个家族中是纯合的，在另一个家族中是复合杂合的。当在体外NB 4嗜中性粒细胞样细胞和EBV转化的B细胞中过表达时，发现突变等位基因是LOF，除了p.R58C和c.120_134del等位基因是亚型的。颗粒诱导的NADPH氧化酶活性在患者的中性粒细胞中严重受损，而PMA诱导的二氢罗丹明-1，2，3（DHR）氧化（广泛用作慢性肉芽肿病（CGD）的诊断试验）在患者中正常或轻度受损。此外，EBV转化的B细胞的NADPH氧化酶活性也严重受损，而单核吞噬细胞的NADPH氧化酶活性正常。最后，与CGD患者不同，中性粒细胞对白色念珠菌和烟曲霉菌丝的杀伤作用在这些患者中是保守的。患者患有炎症过度和外周感染，但他们没有任何CGD中所见的侵入性细菌或真菌感染。遗传性p40（phox）缺陷是一种独特的疾病，类似于一种温和的非典型形式的CGD。
Biallelic loss-of-function (LOF) mutations of the NCF4 gene, encoding the p40(phox) subunit of the phagocyte NADPH oxidase, have been described in only 1 patient. We report on 24 p40(phox)-deficient patients from 12 additional families in 8 countries. These patients display 8 different in-frame or out-of-frame mutations of NCF4 that are homozygous in 11 of the families and compound heterozygous in another. When overexpressed in NB4 neutrophil-like cells and EBV-transformed B cells in vitro, the mutant alleles were found to be LOF, with the exception of the p.R58C and c.120_134del alleles, which were hypomorphic. Particle-induced NADPH oxidase activity was severely impaired in the patients' neutrophils, whereas PMAinduced dihydrorhodamine-1,2,3 (DHR) oxidation, which is widely used as a diagnostic test for chronic granulomatous disease (CGD), was normal or mildly impaired in the patients. Moreover, the NADPH oxidase activity of EBV-transformed B cells was also severely impaired, whereas that of mononuclear phagocytes was normal. Finally, the killing of Candida albicans and Aspergillus fumigatus hyphae by neutrophils was conserved in these patients, unlike in patients with CGD. The patients suffer from hyperinflammation and peripheral infections, but they do not have any of the invasive bacterial or fungal infections seen in CGD. Inherited p40(phox) deficiency underlies a distinctive condition, resembling a mild, atypical form of CGD.