The molecular causes of autosomal-dominant hypertension with brachydactyly (OMIM 112410)

我们正在与一个土耳其家庭，有常染色体显性高血压和短指（OMIM 112410），受影响的人死于中风的年龄在50岁之前。我们将该位点定位于染色体12p，并在临床研究中确定高血压与原发性高血压非常相似。骨骼表型的特征是E型短指和身材矮小。我们招募了更多的家庭来缩小疾病的范围。基因组区域跨越18个注释基因。突变分析进行了15个或多或少有希望的候选基因在5个不同的家庭，但没有被found.With间期FISH，我们现在已经发现了一个重排染色体12 p的缺失，重新插入，并在土耳其家庭的受影响的人倒位。我们还检测到染色体重排受影响的人从另外两个家庭。这三个家庭的重排模式是不同的，但他们都有一个共同的区域。我们将进行经典的定位克隆方法来确定潜在的基因的综合征。该方案的主要任务是克隆和精确表征复杂重排的所有断点。将进行间期和纤维FISH以及Southern印迹，以缩小断点间隔。反向PCR和测序将允许断裂点的精确表征、重排片段的鉴定以及它们与所涉及基因的相对位置。

We are working with a Turkish family that has autosomal-dominant hypertension and brachydactyly (OMIM 112410); affected persons die of stroke before age 50 years. We mapped the locus to chromosome 12p and in clinical studies determined that the hypertension strongly resembles essential hypertension. The skeletal phenotype is characterized by brachydactyly type E and short stature. We recruited more families to narrow down the disease locus to the minimum. The genomic region spans 18 annotated genes. Mutation analysis was performed in 15 of more or less promising candidate genes in five different families, however none were found. With interphase FISH, we have now discovered a rearrangement on chromosome 12p with a deletion, a reinsertion, and an inversion in affected persons of the Turkish family. We also detected chromosomal rearrangements in affected persons from two additional families. The pattern of the rearrangements in these three families are different; however, they all share a common region. We will perform the classical positional cloning approach to identify the underlying gene(s) of the syndrome. The major task of the proposal is to clone and precisely characterize all breakpoints of the complex rearrangements. Interphase- and Fiber-FISH, as well as Southern blots, will be performed to narrow the breakpoint intervals. Inverse PCR and sequencing will allow precise characterization of the breakpoints, the identification of the rearranged fragments, and their relative position to the genes involved.