GENETIC ANALYSIS OF IMMUNODEFICIENCY DISEASES

几种先天性免疫缺陷疾病在一种 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连锁淋巴增殖性综合征(XLP)，以及高- 免疫球蛋白综合征。遗传咨询、围产期管理 如果携带携带者，受影响的婴儿和基因图谱将会更方便 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女性杂合子的正常表型 而Wa是由于突变基因所在的细胞失败所致 活跃的X染色体进入成熟细胞库。这 这些发现将构成诊断本病的三种方法的基础 运营商状态。第一条要求两条X染色体 被分开，以便可以识别活动和非活动的X 通过限制性片段长度多态(RFLP)。这将是 用HPRT-啮齿动物制成的体细胞杂交实现 来自携带者及其亲属的细胞和淋巴细胞。因为 X染色体RFLP丰富这种方法的携带者 每个女性都会成功进行检测，但不会那么费力 还将研究基于DNA甲基化的技术 模式和检测RNA中的多态。最多的 分析X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的区域本地化成为可能 与RFLP的连锁分析以及图谱的改进 XLA、WA、XLP的职位。改进的运营商确定将 也有助于对异质性、新的突变率和 X连锁免疫缺陷新突变的来源。

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.