Hypertension requires increased systemic vascular resistance. Thus far, Mendelian hypertension-related genes are related to salt retention, an indirect regulatory effect. With the identification of mutated, overactive, PDE3A (phosphodiesterase 3A), we have uncovered a more direct vasoconstrictive mechanism. The autosomal-dominant syndrome features another specific phenotype, brachydactyly type E. Hypertension and the bony phenotype invariably occur together. We distinguished between these phenotypes by examining individual pedigrees. We implicated the gene encoding the parathyroid hormone-related peptide in the brachydactyly. We identified the hypertensive mechanisms as involving regulatory-region, gain-of-function, exon 4 rare pathogenic variants, in the cAMP-cGMP-catabolizing enzyme, PDE3A. We generated rodent models that recapitulate all human phenotypes. Comparisons not only allowed pathogenic insights into the human condition but also provided intervention models. Moreover, we identified rare pathogenic variants in exon 13 encoding the enzymatic pocket. These patients had identical phenotypes, also corroborated in a rodent model, which produced the same human phenotypes. These data could allow the differentiation between a target organ and blood pressure phenotype. The research allows visualization of enzymatic processes at the intracellular nanodomain level. The scope of this project has elucidated genetic mechanisms important to cartilage development, possibly cancer metastases, and findings relevant to cardiovascular regulation via systemic vascular resistance. For our team, the project was an educational/scientific adventure over a professional lifetime.

中文翻译：

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个人遗传高血压：从表型到基因型和目标的奥德赛。


高血压需要增加全身血管阻力。到目前为止，孟德尔高血压相关基因与盐潴留有关，这是一种间接的调节作用。随着突变、过度活跃的 PDE3A （磷酸二酯酶 3A） 的鉴定，我们发现了一种更直接的血管收缩机制。常染色体显性遗传综合征具有另一种特异性表型，即短指 E 型高血压和骨表型总是同时发生。我们通过检查单个家系来区分这些表型。我们将编码甲状旁腺激素相关肽的基因与短指有关。我们确定了高血压机制涉及 cAMP-cGMP 分解代谢酶 PDE3A 中的调节区、功能获得、外显子 4 罕见致病性变异。我们生成了概括所有人类表型的啮齿动物模型。比较不仅可以深入了解人类状况的致病性，还可以提供干预模型。此外，我们在编码酶袋的外显子 13 中鉴定了罕见的致病性变异。这些患者具有相同的表型，也证实了啮齿动物模型，该模型产生了相同的人类表型。这些数据可以区分靶器官和血压表型。该研究允许在细胞内纳米结构域水平上可视化酶促过程。该项目的范围阐明了对软骨发育很重要的遗传机制，可能是癌症转移，以及与通过全身血管阻力进行心血管调节相关的发现。对于我们的团队来说，该项目是职业生涯中的一次教育/科学冒险。