Departments of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA.
Department of Endocrinology and Metabolism, National Hospital Organization Kyoto Medical Center, Kyoto, Japan.
Eur J Endocrinol. 2021 May 21;185(1):R1-R11. doi: 10.1530/EJE-21-0031.
Primary aldosteronism (PA) is a common cause of secondary hypertension. Recent technological advances in genetic analysis have provided a better understanding of the molecular pathogenesis of this disease. The application of next-generation sequencing has resulted in the identification of somatic mutations in aldosterone-producing adenoma (APA), a major subtype of PA. Based on the recent findings using a sequencing method that selectively targets the tumor region where aldosterone synthase (CYP11B2) is expressed, the vast majority of APAs appear to harbor a somatic mutation in one of the aldosterone-driver genes, including KCNJ5, ATP1A1, ATP2B3, CACNA1D, CACNA1H, and CLCN2. Mutations in these genes alter intracellular ion homeostasis and enhance aldosterone production. In a small subset of APAs, somatic activating mutations in the CTNNB1 gene, which encodes β-catenin, have also been detected. Accumulating evidence suggests that race and sex impact the somatic mutation spectrum of APA. Specifically, somatic mutations in the KCNJ5 gene, encoding an inwardly rectifying K+ channel, are common in APAs from Asian populations as well as women regardless of race. Associations between APA histology, genotype, and patient clinical characteristics have also been proposed, suggesting a potential need to consider race and sex for the management of PA patients. Herein, we review recent findings regarding somatic mutations in APA and discuss potential roles of race and sex on the pathophysiology of APA as well as possible clinical implications.
原醛症（PA）是继发性高血压的常见病因。近年来，遗传分析技术的进步使人们对该病的分子发病机制有了更好的了解。下一代测序技术的应用已经确定了醛固酮瘤（APA）中的体细胞突变，APA 是 PA 的主要亚型之一。基于最近使用一种选择性靶向醛固酮合酶（CYP11B2）表达区域的测序方法的发现，绝大多数 APA 似乎都携带有一个醛固酮驱动基因中的体细胞突变，包括 KCNJ5、ATP1A1、ATP2B3、CACNA1D、CACNA1H 和 CLCN2。这些基因的突变改变了细胞内离子稳态并增强了醛固酮的产生。在一小部分 APA 中，还检测到编码β-连环蛋白的 CTNNB1 基因的体细胞激活突变。越来越多的证据表明，种族和性别会影响 APA 的体细胞突变谱。具体来说，编码内向整流钾通道的 KCNJ5 基因的体细胞突变在亚洲人群以及无论种族的女性的 APA 中很常见。APA 组织学、基因型和患者临床特征之间的关联也已经被提出，这表明在管理 PA 患者时可能需要考虑种族和性别。在此，我们回顾了 APA 中体细胞突变的最新发现，并讨论了种族和性别对 APA 病理生理学的潜在作用以及可能的临床意义。
