Molecular analysis in three cases of X91- variant chronic granulomatous disease.
Molecular analysis in three cases of X91- variant chronic granulomatous disease.
复制标题
X91 变异慢性肉芽肿病三例的分子分析。
作者：
H. N. Bu;A. Segal;N. Keep;C. Casimir
细胞色素b558(b-245)的大亚基gp91-Phox的缺陷会导致X连锁慢性肉芽肿病(CGD)，这是一种罕见的遗传性疾病，其特征是对细菌和真菌感染极其敏感。在大多数情况下，吞噬细胞由于完全没有黄色素而不能产生任何超氧化物。然而，这些患者中的一小部分确实有吞噬细胞氧化酶的活性。我们在这里描述了三个这种变异患者的疾病的分子基础的分析，这些患者在X染色体上编码gp91-Phox的基因有损害。发现了三种不同的遗传损伤，分别导致酪氨酸取代半胱氨酸244，三种赖氨酸313到315中的一种缺失，以及六个C末端氨基酸的缺失。这些缺陷对氧化酶活性的功能后果是分别降低到正常水平的12%、3.6%和2.1%。相应的gp91-Phox水平分别为正常的20%、8%和16%，将这些患者归类为X91-。杀菌试验表明，在活性为12%的细胞中，对金黄色葡萄球菌的杀灭作用明显减弱。这意味着，如果要应用基因治疗，就必须将氧化酶活性恢复到比患者细胞中目前的水平高得多的水平。根据同源蛋白质亚铁还蛋白NADP还原酶的晶体结构，在gp91-Phox的C末端一半的模型上分析了其中两个突变的位置。研究了突变可能产生的结构性后果。
Defects in gp91-phox, the large subunit of cytochrome b558 (b-245) give rise to X-linked chronic granulomatous disease (CGD), a rare inherited condition characterized by an extreme susceptibility to bacterial and fungal infection. In the majority of cases, the phagocytes are unable to generate any superoxide owing to complete absence of the flavocytochrome. However, a small minority of these patients do have some phagocytic oxidase activity. We describe here an analysis of the molecular basis of the disease in three such variant patients with lesions in the gene coding for gp91-phox on the X chromosome. Three different genetic lesions were found, resulting in the substitution of tyrosine for cysteine 244, a deletion of one of three lysines 313 through 315, and the deletion of the six C-terminal amino acids, respectively. The functional consequences of these defects on oxidase activity was a reduction to 12%, 3.6%, and 2.1% of the normal levels, respectively. Corresponding levels of gp91-phox were 20%, 8%, and 16% of normal classifying these patients as X91-. Microbicidal assays showed that killing of Staphylococcus aureus was grossly impaired in cells in which there was 12% normal activity. This implies that if gene therapy is to be applied, it must restore oxidase activity to a much higher level than that present in the cells of this patient. The sites of two of the mutations were analyzed on a model of the C-terminal half of the gp91-phox, based on the crystal structure of the homologous protein ferrodoxin NADP reductase. Possible structural consequences of the mutations were examined.
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DOI：
10.1097/00006454-198411000-00015
发表时间：
1984
期刊：
Pediatric infectious disease
影响因子：
--
作者：
Styrt,B;Klempner,MS
通讯作者：
Klempner,MS
影响因子：
56.9
作者：
LETO, TL;LOMAX, KJ;MALECH, HL
通讯作者：
MALECH, HL
常染色体慢性肉芽肿病中不存在两种胞质中性粒细胞氧化酶成分。
DOI：
10.1126/science.2848318
发表时间：
1988
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Volpp,BD;Nauseef,WM;Clark,RA
通讯作者：
Clark,RA
慢性肉芽肿性疾病的一种变体：低亲和力 NADPH 氧化酶导致氧化代谢缺陷。
DOI：
10.1056/nejm198111263052207
发表时间：
1981
期刊：
The New England journal of medicine
影响因子：
--
作者：
Lew,PD;Southwick,FS;Stossel,TP;Whitin,JC;Simons,E;Cohen,HJ
通讯作者：
Cohen,HJ
变异型慢性肉芽肿病：严重感染对中性粒细胞缺陷的调节。
影响因子：
20.3
作者：
Newburger,PE;Luscinskas,FW;Ryan,T;Beard,CJ;Wright,J;Platt,OS;Simons,ER;Tauber,AI
通讯作者：
Tauber,AI