PDE3A mutations cause autosomal dominant hypertension with brachydactyly.

Cardiovascular disease is the most common cause of death worldwide, and hypertension is the major risk factor. Mendelian hypertension elucidates mechanisms of blood pressure regulation. Here we report six missense mutations in PDE3A (encoding phosphodiesterase 3A) in six unrelated families with mendelian hypertension and brachydactyly type E (HTNB). 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. In vitro analyses of mesenchymal stem cell-derived vascular smooth muscle cells (VSMCs) and chondrocytes provided insights into molecular pathogenesis. The mutations increased protein kinase A-mediated PDE3A phosphorylation and resulted in gain of function, with increased cAMP-hydrolytic activity and enhanced cell proliferation. Levels of phosphorylated VASP were diminished, and PTHrP levels were dysregulated. We suggest that the identified PDE3A mutations cause the syndrome. VSMC-expressed PDE3A deserves scrutiny as a therapeutic target for the treatment of hypertension.

Phacoemulsification does not induce neovascular age-related macular degeneration.

PURPOSE: To investigate whether cataract surgery by phacoemulsification induces progression of early age-related macular degeneration (AMD) to neovascular AMD. METHODS: Retrospective case-control study. Included were consecutive patients who had undergone phacoemulsification from January 2000 to February 2006 at the Recklinghausen Eye Centre, who had a preexisting diagnosis of early AMD and who were followed up for at least 1 year after surgery (n = 1152 eyes of 696 patients). The control group comprised phakic patients diagnosed with early AMD from January 2000 to February 2006, who did not undergo eye surgery and were followed up for at least 1 year (n = 334 eyes of 202 patients). RESULTS: At baseline, control eyes had significantly better visual acuity than those of patients who were going to have cataract surgery (0.30/0.35 +/- 0.34 vs. 0.40/0.49 +/- 0.34, respectively; median/mean +/- SD; P < 0.001, Mann-Whitney rank sum test). After 1 year, visual acuity in the control group was worse than in surgical eyes (0.30/0.39 +/- 0.38 vs. 0.20/0.26 +/- 0.30, respectively; median/mean +/- SD; P < 0.001, Mann-Whitney rank sum test). In the cataract surgery group, neovascular AMD developed in 28 (2.43%) of 1152 eyes in the first postoperative year. In the control group, it developed in 6 (1.74%) of 344 eyes within 1 year. There was no significant difference between the groups in the incidence of neovascular AMD (P = 0.57, odds ratio 1.30, 95% CI 0.52-3.24, logistic regression analysis, adjusted for age and baseline visual acuity). CONCLUSIONS: The results indicate that cataract surgery in eyes with early AMD is not a causative factor in neovascular AMD.