MOLECULAR GENETICS--INHERITED FOCAL GLOMERULOSCLEROSIS

这项建议的主要目标是确定一个或多个基因 导致局灶节段性肾小球硬化 （FSGS）在常染色体显性遗传的家庭中， 条件这项工作的基本假设是， 单基因形式的FSGS的病因学将产生相当大的， 新的信息进入生物途径负责更常见的 FSGS的形式，包括FSGS的二级形式，以及 由糖尿病和高血压引起的肾小球硬化。我们有 鉴定，临床特征，并收集DNA样本，从一个 很多家庭都有这种情况。在最大的两个 家庭，我们已经将负责基因定位到3.5厘摩， 人类19号染色体区域。连锁分析在其他几个 家庭表明，这个位点不窝藏缺陷基因， 所有家庭都有FSGS。 我们打算在19号染色体上精确定位FSGS基因 通过鉴定额外的重组事件来鉴定基因座。为实现这一 我们将扩大研究中的家庭，并继续收集 更多的家庭。我们将构建BAC重叠群，以补充现有的 染色体19q13区域的物理和遗传图谱， EST，STS，微卫星和基因在这个区间内。我们将 然后通过基因鉴定组合来鉴定FSGS基因， 方法和序列分析。接下来我们将在其他细胞中检测该基因。 FSGS的小家庭和患有原发性和继发性 FSGS。 鉴定一个基因，负责肾功能不全，在这些 家庭将确定一种新的生物学途径， 局灶节段性肾小球硬化这些研究将确定基因 对于以前未认识到的肾衰竭原因，提供见解 肾小球硬化症的生物学，并确定一种生物学， 遗传途径，这可能是负责一个显着的比例， 肾功能不全的人群。

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.