MOLECULAR GENETICS--INHERITED FOCAL GLOMERULOSCLEROSIS

这个提议的主要目标是识别一个或多个基因。 局灶性节段性肾小球硬化的发病机制 常染色体显性遗传的家系(FSGS) 条件。这项工作的基本假设是，识别 单基因形式的FSGS的病因学将产生相当大的和 新奇的信息进入生物通路的责任更常见 FSGS的形式，包括FSGS的次要形式以及 糖尿病和高血压引起的肾小球硬化。我们有 鉴定、临床特征和收集的DNA样本 有这种情况的家庭很多。在最大的两个 家庭，我们已经将负责的基因定位在3.5厘米长的 人类19号染色体区域。其他几个区域的连锁分析 家系研究表明，该基因座不存在缺陷基因。 所有患有FSGS的家庭。 我们打算将FSGS基因定位在这条19号染色体上 通过识别额外的重组事件来定位。朝向这个方向 目标我们将扩大正在研究的家庭，并继续收集 其他家庭。我们将构建一个BAC重叠群来补充现有的 染色体19q13区域的物理和遗传图谱，以便作图 EST、STSS、微卫星和该区间内的基因。我们会 然后结合基因鉴定对FSGS基因进行鉴定 方法和序列分析。接下来我们将研究其他基因中的这种基因 患有FSGS的小家庭和患有小学和中学的个人 FSGS。 在这些患者中发现一个与肾功能障碍有关的基因 这些家庭将确定一条新的生物途径来发展 局灶性节段性肾小球硬化。这些研究将确定该基因 对于以前未被发现的肾功能衰竭的原因，提供见解 深入研究肾小球硬化的生物学，并确定一种生物学和 遗传途径可能导致相当大比例的 普通人群中的肾功能障碍。

The principal goal of this proposal is to identify a gene or genes responsible for the development of focal segmental glomerulosclerosis (FSGS) in families with autosomal dominant inheritance of this condition. The underlying hypothesis of this work is that identifying the etiology of single-gene forms of FSGS will yield considerable and novel information into the biologic pathways responsible for more common forms of FSGS, including secondary forms of FSGS, as well as glomerulosclerosis resulting from diabetes and hypertension. We have identified, clinically characterized, and collected DNA samples from a large number of families with this condition. In the largest two families, we have mapped the responsible gene to a 3.5 centimorgan region of human chromosome 19. Linkage analysis in several other families indicate that this locus does not harbor the defective gene in all families with FSGS. We intend to refine the location of the FSGS gene at this chromosome 19 locus by identification of additional recombination events. Towards this goal we will expand the families under study and continue to collect additional families. We will build a BAC contig to complement the exist physical and genetic map of the chromosome 19q13 region in order to map ESTs, STSs, microsatellites, and genes within this interval. We will then identify the FSGS gene by a combination of gene identification methods and sequence analysis. We will next examine this gene in other small families with FSGS and individuals with primary and secondary FSGS. Identification of a gene responsible for renal dysfunction in these families will identify a novel biologic pathway in the development of focal segmental glomerulosclerosis. These studies will identify the gene for a previously unrecognized cause of renal failure, provide insight into the biology of glomerulosclerosis, and identify a biologic and genetic pathway which may be responsible for a significant proportion of renal dysfunction in the general population.