Since 1994, we have pursued a Mendelian form of hypertension that cosegregates with brachydactyly type E (HTNB). We recently reported six missense mutations in PDE3A (encoding phosphodiesterase 3A) in six unrelated families with HTNB (Nat Genet 2015). The syndrome features brachydactyly type E (BDE), severe salt-independent but age-dependent hypertension, an increased fibroblast growth rate, neurovascular contact at the rostral-ventrolateral medulla, altered baroreflex blood pressure regulation, and death from stroke before age 50 years when untreated. This project promises to open new avenues in terms of elucidating high blood pressure and suggesting novel treatments.
We are also interested in epigenetics, particularly in the role of altered inter-chromosomal interactions as a cause of human disease. In addition, we have investigated the role of salt intake on blood pressure in terms of body sodium storage and effects on metabolism. Finally, we are developing novel animal models to investigate unexplored mechanisms that increase peripheral vascular resistance.
We are pursuing the molecular genetics of hypertension and brachydactyly, two phenotypes which are closely linked in a family we discovered over 15 years ago. Hypertension and the organ damage that ensue from it are tremendously challenging topics for research because they arise through an interaction between many genes and environmental factors. This project began as a classic search for a mutation in a gene and has led us to new insights into one of the most interesting current themes in science: the epigenetic regulation of the genome.
While trying to explain the brachydactyly phenotype, we discovered a series of very complex cis- and trans-regulatory epigenetic phenomena; they may serve as a model system to explore important open questions about genome architecture and regulation. In addition, collaborations that Friedrich C. Luft initiated with the University of Erlangen and Vanderbilt University has led to some exciting and unexpected findings in terms of bodily sodium homeostasis.
Since our report, we have identified another six families with HTNB, increasing our total number to 12 unrelated families worldwide. One family has a mutation in the cleavage site of PDE3A, while all the others have mutations within the 15 bp segment that we identified as encoding a regulatory region of phosphorylation. These exciting findings promise to allow further elucidation how the syndrome works.
We have good reason to believe our findings are relevant for patients with “essential” hypertension (without short fingers). We have collected large kindreds from China with essential hypertension and mapped their blood pressure phenotype to our locus. We also focus our research on these families. In addition, four independent genome-wide association studies implicate our locus. Finally, we have four animal models focusing on PDE3A under development.
We have had a long interest in inter-chromosomal interactions as a cause for human disease. This work is spearheaded by Philipp Maass, who has since moved to the Broad Institute in Boston, MA, USA. We recently focused on a three-generation family harboring a 2q37-deletion syndrome, featuring a heterozygous partial deletion of histone deacetylase 4 (HDAC4) on chr2q37. The clinical phenotype is brachydactyly type E, but without hypertension. The data we have generated provide evidence for the impact of genomic rearrangements and their consequence on repositioning loci locally within the genomic architecture. Our findings provide evidence for a direct link between a structural chromosomal aberration and altered interphase architecture that results in a nuclear configuration, supporting a possible molecular pathogenesis.
Salt intake has long been implicated in the development of hypertension. Our group is also collaborating on elucidating salt-related mechanisms causing elevated blood pressure. This work is performed in conjunction with Vanderbilt University School of Medicine, Nashville, TN, USA. Here we are using a novel magnetic resonance technique to measure body sodium stores. We recently showed that salt intake influences metabolism leading to urea and water production in man (J Clin Invest 2017) and animals (J Clin Invest 2017).