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

阿尔波特遗传性肾炎的医学遗传学认识 综合症在过去的四年里发展迅速，随着这一发现 1990年发现的次要基底膜(BM)胶原基因Col4A5，定位于 在X染色体的Q22带上。到目前为止，有50多个不同的Alport 在Col4A5中发现了综合征突变。现在看来， COL4A5或第二个BM胶原基因COL4A6的突变 紧邻Col4A5的将显示占多数 阿尔波特综合征，因为大多数家庭都表现出遗传连锁 转到XQ22。然而，并不是所有的Alport综合征都是由Xq22缺陷引起的。 一种罕见的常染色体隐性遗传性疾病已被证明是 由2号染色体上的COL4A3或COL4A4基因突变引起。 也是常染色体显性遗传形式可能解释的遗传证据 约15%的病例。建国初期的两大成就 该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遗传多样性的收集 一组适合进行基因组连锁搜索的家系样本 常染色体显性基因(S)。进一步发展的主要目标 这里提出的研究是继续阿尔波特的遗传分类 家庭，以确定其他常染色体亲属并将其包括在内 那些已经在基因组连锁搜索中发现的基因 常染色体显性基因座。具有X链接形式的族 疾病将被包括在突变研究中，以确定 COL4A5(或COL4A6)缺陷。努力的方向将是 建立简单有效的Col4A5突变筛选策略 基因(如果合适的话，还有COL4A6)来改进遗传诊断 潜力。突变筛查倡议的第二个目的是 提供一种独立的测试，以确定看起来像是 遗传标记分析显示，与Xq22未连锁的基因可能仍包括一些 受影响的个体具有Col4A5基因改变。在以后的阶段， ，我们计划进行基因精细作图，以提炼 任何新的Alport基因的定位)通过基因组搜索鉴定)S 然后对合适的基因进行突变筛选。

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.