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

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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.