Published Online
on January 5, 2004

A more recent version of this article appeared on February 1, 2004

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Submitted on September 30, 2003
Revised on October 31, 2003

Autosomal-Dominant Hypertension With Type E Brachydactyly Is Caused by Rearrangement on the Short Arm of Chromosome 12

Sylvia Bähring; Anita Rauch; Okan Toka; Christoph Schroeder; Christiane Hesse; Heike Siedler; Gabor Fesüs; Walter E. Haefeli; Andreas Busjahn; Atakan Aydin; Yvette Neuenfeld; Astrid Mühl; Hakan R. Toka; Maik Gollasch; Jens Jordan; and Friedrich C. Luft^*

From the Medical Faculty of the Charité, The Clinical Research Center, Franz Volhard Clinic and the Max Delbrück Center for Molecular Medicine (S.B., O.T., C.S., G.F., A.B., A.A., Y.N. A.M., H.R.T., M.G., J.J., F.C.L.), HELIOS Klinikum, Berlin, Germany; the Department of Genetics (A.R.), University of Erlangen, Germany; and the Department of Internal Medicine VI (C.H., H.S., W.E.H.), Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Germany.

^* To whom correspondence should be addressed. E-mail: luft{at}fvk-berlin.de.

Abstract--We are studying a Turkish family with autosomal-dominant hypertension and brachydactyly; affected persons die of stroke before 50 years of age. With interphase fluorescence in situ hybridization, we found a chromosome 12p deletion, reinsertion, and inversion in affected persons. This finding suggested that the hypertension could be caused by one or more of 3 genes, the ATP-dependent potassium channel Kir6.1, its regulator the sulfonyl urea receptor SUR2, and the phosphodiesterase PDE3A. We further studied 6 affected and 4 nonaffected persons. Buttocks biopsies were done, small vessels were tested on a myograph, and mRNA was extracted. We performed forearm blood flow studies with intrabrachial artery diazoxide, isoproterenol, and milrinone infusions. Systemic pharmacological testing was done with intravenous diazoxide, nitroprusside, and isoproterenol. PDE3A mRNA was high in vessels from 3 affected subjects, but not high in 3 others. The vessels responded similarly to forskolin, with or without glibenclamide, and to cromakalim. However, there was a suggestion that the dilatation after milrinone might be exaggerated. The forearm infusion studies showed no differences in the responses to diazoxide, isoproterenol, or milrinone. Systemically, affected persons showed a greater blood pressure response to diazoxide and nitroprusside, and a greater heart rate response to isoproterenol than nonaffected persons. The results shed doubt on Kir6.1 and SUR2. The differences in PDE3A expression and responses may be the result of hypertension rather than the cause. Although our 3 candidate genes are no longer likely, the rearrangement we describe greatly enhances the perspectives of this project.

Key words: hypertension • genetics • gene expression

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