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

我们正在与一个患有常染色体显性高血压和短指畸形的土耳其家庭合作（OMIM 112410）；受影响的人在50岁之前死于中风。我们将其定位到12p染色体，并在临床研究中确定高血压与原发性高血压非常相似。骨骼表型的特点是短指型E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。对5个不同家族的15个或多或少有希望的候选基因进行了突变分析，但没有发现。通过间期FISH，我们在土耳其家族的受影响人群中发现了12p染色体的重排，缺失，重新插入和倒置。我们还在另外两个家族的患者中检测到染色体重排。这三个家族的重排模式不同；然而，它们都有一个共同的区域。我们将执行经典的定位克隆方法，以确定潜在的基因(s)的综合征。该建议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印迹来缩小断点间隔。反向PCR和测序将允许精确表征断点，鉴定重排片段，以及它们与相关基因的相对位置。

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.