GENETIC ANALYSIS OF IMMUNODEFICIENCY DISEASES

几种先天性免疫缺陷疾病是遗传在一个 X连锁隐性时尚，包括最常见的形式， 严重联合免疫缺陷病（XSCID）和 无丙种球蛋白血症（XLA）以及Wiskott Aldrich综合征 (WA)、X连锁淋巴组织增生综合征（XLP）和超- IgM综合征。 遗传咨询、围产期管理 受影响的婴儿和基因图谱将有助于如果携带者 检测测试是可用的，但这些女性携带者 疾病是完全正常的。 初步研究表明， XSCID、XLA女性杂合子正常表型 而WA是由于突变基因启动的细胞的失败， 活跃的X染色体进入成熟细胞库。 这 这一发现将构成三种诊断方法的基础。 的载体状态。 第一个要求两条X染色体 分离，以便可以识别活动和非活动X 限制性片段长度多态性（RFLP）。 这将 用HPRT-啮齿动物制成的体细胞杂交体实现 细胞和淋巴细胞从携带者和他们的亲属。 因为 X染色体RFLP是丰富的这种方法的载体 每一个女性检测都会成功，但不那么费力 基于DNA甲基化的技术也将继续发展 模式和检测RNA中的多态性。 最 分析X染色体失活模式的有效技术将是 用于确定高危女性的携带者状态。 这 信息将使XSCID的区域定位成为可能， 利用RFLP进行连锁分析，并对图谱进行细化 XLA、WA、XLP的位置。 改进的承运人确定将 也有助于异质性、新突变率和 X-连锁免疫缺陷的新突变来源。

Several congenital immunodeficiency diseases are inherited in an X linked recessive fashion, including the most common forms of severe combined immunodeficiency disease (XSCID) and agammaglobulemia (XLA), as well as Wiskott Aldrich syndrome (WA), X linked lymphoproliferative syndrome (XLP), and hyper- IgM syndrome. Genetic counselling, perinatal management of affected infants and gene mapping would be facilitated if carrier detection tests were available, but female carriers of these diseases are completely normal. Preliminary studies indicate that the normal phenotype of female heterozygotes in XSCID, XLA and WA is due to failure of cells in which the mutant gene is on the active X chromosome to enter the mature cell pool. This finding will form the basis for three approaches to diagnosis of the carrier state. The first requires that the two X chromosomes be separated so that the active and inactive X can be identified by restriction fragment length polymorphisms (RFLPs). This will be achieved with somatic cell hybrids made from HPRT-rodent cells and lymphocytes from carriers and their relatives. Because X chromosome RFLPs are abundant this method of carrier detection will succeed in every women, but less laborious techniques will also be pursued based on DNA methylation patterns and on detection of polymorphisms in RNA. The most efficient technique for assaying X inactivation pattern will be used to determine carrier status of at-risk females. This information will make possible regional localization of XSCID by linkage analysis with RFLPs as well as refinement of the map position of XLA, WA, XLP. Improved carrier ascertainment will also aid genetic studies of heterogeneity, new mutation rates and source of new mutations in X-linked immunodeficiencies.