Personal Genetic-Hypertension Odyssey From Phenotypes to Genotypes and Targets.

IF 6.9 1区 医学 Q1 PERIPHERAL VASCULAR DISEASE Hypertension Pub Date : 2024-12-01 Epub Date: 2024-10-02 DOI:10.1161/HYPERTENSIONAHA.124.21714
Friedrich C Luft
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Abstract

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.

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从表型到基因型和目标的个人遗传高血压奥德赛。
高血压需要全身血管阻力增加。迄今为止,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)的发现,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还具有另一种特殊的表型--E 型肱骨发育不良。我们通过研究个体血统来区分这些表型。我们发现编码甲状旁腺激素相关肽的基因与手足畸形有关。我们发现,高血压的发病机制涉及 cAMP-cGMP 分解酶 PDE3A 的调节区、功能增益、第 4 外显子罕见致病变异。我们制作的啮齿动物模型再现了人类的所有表型。通过比较不仅可以了解人类的致病情况,还可以提供干预模型。此外,我们还在编码酶袋的第 13 号外显子中发现了罕见的致病变体。这些患者具有相同的表型,在啮齿动物模型中也得到了证实,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。通过这项研究,可以在细胞内纳米域水平上实现酶过程的可视化。这个项目的研究范围已经阐明了对软骨发育非常重要的遗传机制、可能的癌症转移,以及通过全身血管阻力调节心血管的相关发现。对我们团队来说,该项目是一次跨越职业生涯的教育/科学探险。
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来源期刊
Hypertension
Hypertension 医学-外周血管病
CiteScore
15.90
自引率
4.80%
发文量
1006
审稿时长
1 months
期刊介绍: Hypertension presents top-tier articles on high blood pressure in each monthly release. These articles delve into basic science, clinical treatment, and prevention of hypertension and associated cardiovascular, metabolic, and renal conditions. Renowned for their lasting significance, these papers contribute to advancing our understanding and management of hypertension-related issues.
期刊最新文献
Awakening to the Pertinence of Sleep for Hypertension. Renal Medulla in Hypertension. Personal Genetic-Hypertension Odyssey From Phenotypes to Genotypes and Targets. Water and Electrolyte Content in Hypertension in the Skin (WHYSKI) in Primary Aldosteronism. Aortic-Femoral Stiffness Gradient and Cardiovascular Risk in Older Adults.
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