Dinauer M C, Orkin S H
Howard Hughes Medical Institute, Children's Hospital, Harvard Medical School, Boston, MA 02115.
Immunodefic Rev. 1988;1(1):55-69.
Chronic granulomatous disease is an inherited disorder characterized by the failure of phagocytic cells to produce superoxide upon the ingestion of microorganisms due to a lesion in a membrane-associated NADPH-oxidase. The components of the oxidase have been incompletely characterized by standard biochemical approaches. A genetic strategy has recently led to the identification of the gene affected in the common X-linked form of CGD without reference to its protein product. The X-CGD gene, assigned to chromosome position Xp21.1, encodes a phagocyte-specific RNA transcript that is mutated in patients with X-CGD. Antisera directed toward the predicted protein product of the X-CGD gene recognize a 90 kD membrane glycoprotein, which corresponds to the larger subunit of the phagocyte b-cytochrome heterodimer. The recent genetic and biochemical findings provide an explanation for the consistent absence of the b-cytochrome spectrum in X-CGD, and establish this cytochrome as an essential component of the phagocyte oxidase. The primary amino acid sequence of both the 90 kD b-cytochrome subunit and the 22 kD subunit (cloned as the cDNA using a specific antisera) have no significant similarity to other proteins, including previously studied cytochromes. As both subunits of the b-cytochrome heterodimer are absent in X-CGD, despite a genetic deficiency of only the larger polypeptide, a close interaction between the two subunits may be important for b-cytochrome stability and function. Expression of the b-cytochrome large subunit mRNA is increased by interferon-gamma, an important macrophage activator. Partial or complete restoration of oxidase activity in some X-CGD patients treated with interferon-gamma suggests new therapeutic approaches in the management of this disorder. Molecular reagents prepared from the cloned X-CGD cDNA or gene may prove to be clinically useful in prenatal diagnosis and may provide a basis for somatic gene therapy in future.
慢性肉芽肿病是一种遗传性疾病，其特征是吞噬细胞在摄入微生物时，由于膜相关NADPH氧化酶的损伤而无法产生超氧化物。氧化酶的成分尚未通过标准生化方法完全鉴定。最近，一种基因策略已导致在不参考其蛋白质产物的情况下，鉴定出常见X连锁形式的慢性肉芽肿病中受影响的基因。位于Xp21.1染色体位置的X连锁慢性肉芽肿病基因编码一种吞噬细胞特异性RNA转录本，该转录本在X连锁慢性肉芽肿病患者中发生突变。针对X连锁慢性肉芽肿病基因预测蛋白质产物的抗血清识别一种90kD的膜糖蛋白，该蛋白对应于吞噬细胞b-细胞色素异二聚体的较大亚基。最近的基因和生化研究结果为X连锁慢性肉芽肿病中一致缺乏b-细胞色素光谱提供了解释，并将这种细胞色素确立为吞噬细胞氧化酶的重要组成部分。90kD的b-细胞色素亚基和22kD亚基（使用特异性抗血清克隆为cDNA）的一级氨基酸序列与其他蛋白质没有显著相似性，包括先前研究的细胞色素。尽管在X连锁慢性肉芽肿病中仅存在较大多肽的基因缺陷，但b-细胞色素异二聚体的两个亚基均不存在，这表明两个亚基之间的紧密相互作用可能对b-细胞色素的稳定性和功能很重要。γ干扰素是一种重要的巨噬细胞激活剂，可增加b-细胞色素大亚基mRNA的表达。一些接受γ干扰素治疗的X连锁慢性肉芽肿病患者的氧化酶活性部分或完全恢复，这提示了治疗该疾病的新方法。从克隆的X连锁慢性肉芽肿病cDNA或基因制备的分子试剂可能在产前诊断中具有临床应用价值，并可能为未来的体细胞基因治疗提供基础。
