ALPORT SYNDROME--GENETICS OF X-LINKED AND AUTOSOMAL FORM

遗传性肾炎的医学遗传学理解，Alport 综合征，在过去的四年里迅速发展， 在1990年的小基底膜（BM）胶原基因COL4A5，位于 在X染色体的q22带。 迄今为止，超过50种不同的Alport 在COL4A5中发现了综合征突变。 现在看来 C0L4A5或第二BM胶原基因C0L4A6中的突变，其位于 与COL4A5紧邻，将显示占大多数 Alport综合征，因为大多数家庭显示遗传连锁 XQ22 然而，并非所有的Alport综合征都是由Xq22缺陷引起的。 一种罕见的常染色体隐性形式的疾病已被证明是 由2号染色体上的COL4A3或COL4A4基因突变引起。 那里 也是常染色体显性遗传的遗传证据， 约15%的病例。 这一时期的两大成就 项目已经积累了大量的遗传证据， Alport综合征的遗传异质性和收集 来自一组适合于基因组连锁搜索的激酶的样品， 常染色体显性基因。 进一步的主要目标 这里提出的研究是继续奥尔波特的遗传分类， 家庭，以确定其他常染色体激酶，并包括他们 与那些已经在基因组连锁搜索中确定的位点 常染色体显性遗传基因。 具有X连锁形式的 疾病将被纳入突变研究，以确定 COL4A5（或COL4A6）缺陷。 努力将针对 为COL4A5开发简单有效的突变筛查策略 基因（和COL4A6，如果合适）以改善遗传诊断 潜力 突变筛查的第二个目的是 提供了一个独立的测试，是否家庭似乎是 通过遗传标记分析与Xq22“无关”的基因可能仍然包括一些 受影响的人与COL4A5改变。 在后期阶段， 建议的项目，我们计划进行遗传精细映射，以完善 通过基因组搜索鉴定的任何新Alport基因的定位 然后进行合适基因的突变筛选。

Medical genetic understanding of the inherited nephritis, Alport syndrome, has advanced rapidly in the past four years, with the discovery in 1990 of the minor basement membrane (BM) collagen gene COL4A5, located at the q22 band of the X chromosome. To date, over 50 different Alport syndrome mutations have been found in COL4A5. It now appears that mutations in COL4A5 or a second BM collagen gene COL4A6, that is located immediately adjacent to COL4A5, will be shown to account for the majority of Alport syndrome, since the majority of families show genetic linkage to Xq22. Not all Alport syndrome is caused by defects at Xq22, however. A rare autosomal recessive form of the disease has been shown to be caused by mutations in the COL4A3 or COL4A4 genes on chromosome 2. There is also genetic evidence that an autosomal dominant form may account for about 15% of cases. Two major achievements of the initial period of this project have been the accumulation of substantial genetic evidence for the genetic heterogeneity of Alport syndrome and the collection of samples from a set of kindreds suitable for a genomic linkage search for the autosomal dominant gene(s). Primary objectives of the further research proposed here are to continue the genetic triage of Alport families, to identify additional autosomal kindreds and to include them with those already identified in a genomic linkage search for the site of the autosomal dominant locus. Families with the X-linked form of the disease will be included in mutation studies to determine the nature of the COL4A5 (or COL4A6) defect. Efforts will be directed toward developing simple, effective mutation screening strategies for the COL4A5 gene (and COL4A6, if appropriate) to improve genetic diagnostic potential. A second purpose of the mutation-screening initiative is to provide an independent test of whether families that appear to be 'unlinked' to Xq22 by genetic marker analysis may still include some affected individuals with a COL4A5 alteration. At later stages of the proposed project, we plan to perform genetic fine-mapping to refine the localization of any new Alport gene)s) identified by the genomic search and then conduct mutation-screening of appropriate genes.