van Rooyen Desmaré, Bandulik Sascha, Coon Grace, Laukemper Miriam, Kumar-Sinha Chandan, Udager Aaron M, Lee Chaelin, Wachtel Heather, Cohen Debbie L, Luther James M, Giordano Thomas, Turcu Adina, Warth Richard, Rainey William E, Rege Juilee
bioRxiv. 2024 Oct 23:2024.10.20.619295. doi: 10.1101/2024.10.20.619295.
Primary aldosteronism is characterized by renin-independent hyperaldosteronism that originates from aldosterone-producing lesions in the adrenal glands. Under physiological conditions, aldosterone synthase ( ) expression is confined to the adrenal zona glomerulosa where it catalyzes the final reaction yielding aldosterone. The regulation of transcription depends on the control of cellular membrane potential and cytosolic calcium activity. In primary aldosteronism, aldosterone-producing adenomas (APAs) are characterized by disrupted regulation of CYP11B2 expression resulting in autonomous biosynthesis of aldosterone. These lesions often harbor aldosterone-driver somatic mutations in genes encoding ion transporters/channels/pumps that increase cytosolic calcium activity causing increased expression and aldosterone biosynthesis. We investigated APAs devoid of known somatic mutations and detected a missense mutation and a deletion-insertion variant in which encodes for mucolipin-3 (TRPML3) - a highly conserved inwardly-rectifying, cation-permeable channel. These mutations were identified in three APAs derived from male patients with primary aldosteronism: p. Y391D and p.N411_V412delinsI. Both mutations are located near the ion pore and selectivity filter of TRPML3. This is the first report of disease-causing mutations in humans. Functional studies suggest might directly or indirectly via membrane depolarization alter calcium influx of transfected adrenocortical cells, resulting in increased transcription and aldosterone production. This study implicates mutated as a driver of aldosterone excess in primary aldosteronism.
Primary aldosteronism is a common but under-diagnosed endocrine disease that contributes to global hypertension burden and cardiovascular mortality and morbidity. Hyperaldosteronism in primary aldosteronism is mainly caused by adrenal lesions harboring somatic mutations that disrupt intracellular calcium levels and consequently aldosterone synthase expression and aldosterone production. Majority of these mutations have been identified in genes encoding ion transporters/channels/pumps. Herein, we report the first disease-causing somatic mutations in human in aldosterone-producing adenomas (APAs) devoid of known mutations. investigations showed the variant (p.Y391D) caused an influx of cytosolic calcium in adrenocortical cells and the subsequent increase in aldosterone synthase and aldosterone biosynthesis.
原发性醛固酮增多症的特征是不依赖肾素的醛固酮增多，其源于肾上腺中产生醛固酮的病变。在生理条件下，醛固酮合酶（ ）的表达局限于肾上腺球状带，在那里它催化产生醛固酮的最终反应。 转录的调节取决于细胞膜电位和胞质钙活性的控制。在原发性醛固酮增多症中，产生醛固酮的腺瘤（APA）的特征是CYP11B2表达的调节紊乱，导致醛固酮的自主生物合成。这些病变通常在编码离子转运体/通道/泵的基因中存在醛固酮驱动的体细胞突变，这些突变会增加胞质钙活性，导致 表达增加和醛固酮生物合成增加。我们研究了没有已知体细胞突变的APA，并在编码黏脂素-3（TRPML3）的 中检测到一个错义突变和一个缺失-插入变体，TRPML3是一种高度保守的内向整流、阳离子通透通道。这些 突变在三名患有原发性醛固酮增多症的男性患者的APA中被鉴定出来：p.Y391D和p.N411_V412delinsI。这两个突变都位于TRPML3的离子孔和选择性过滤器附近。这是人类致病 突变的首次报道。功能研究表明， 可能直接或通过膜去极化间接改变转染肾上腺皮质细胞的钙内流，导致 转录增加和醛固酮产生增加。这项研究表明，突变的 是原发性醛固酮增多症中醛固酮过量的驱动因素。
原发性醛固酮增多症是一种常见但诊断不足的内分泌疾病，它导致全球高血压负担以及心血管疾病的死亡率和发病率。原发性醛固酮增多症中的醛固酮增多主要由具有体细胞突变的肾上腺病变引起，这些突变会破坏细胞内钙水平，从而导致醛固酮合酶表达和醛固酮产生增加。这些突变大多数已在编码离子转运体/通道/泵的基因中被鉴定出来。在此，我们报告了在没有已知突变的产生醛固酮的腺瘤（APA）中人类 的首个致病体细胞突变。 研究表明， 变体（p.Y391D）导致肾上腺皮质细胞中胞质钙内流，并随后增加醛固酮合酶和醛固酮生物合成。
