Endocrine Hypertension, Department of Clinical Pharmacology and Precision Medicine, William Harvey Research Institute, Queen Mary University of London, London, UK.
NIHR Barts Biomedical Research Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
Nat Genet. 2023 Jun;55(6):1009-1021. doi: 10.1038/s41588-023-01403-0. Epub 2023 Jun 8.
Aldosterone-producing adenomas (APAs) are the commonest curable cause of hypertension. Most have gain-of-function somatic mutations of ion channels or transporters. Herein we report the discovery, replication and phenotype of mutations in the neuronal cell adhesion gene CADM1. Independent whole exome sequencing of 40 and 81 APAs found intramembranous p.Val380Asp or p.Gly379Asp variants in two patients whose hypertension and periodic primary aldosteronism were cured by adrenalectomy. Replication identified two more APAs with each variant (total, n = 6). The most upregulated gene (10- to 25-fold) in human adrenocortical H295R cells transduced with the mutations (compared to wildtype) was CYP11B2 (aldosterone synthase), and biological rhythms were the most differentially expressed process. CADM1 knockdown or mutation inhibited gap junction (GJ)-permeable dye transfer. GJ blockade by Gap27 increased CYP11B2 similarly to CADM1 mutation. Human adrenal zona glomerulosa (ZG) expression of GJA1 (the main GJ protein) was patchy, and annular GJs (sequelae of GJ communication) were less prominent in CYP11B2-positive micronodules than adjacent ZG. Somatic mutations of CADM1 cause reversible hypertension and reveal a role for GJ communication in suppressing physiological aldosterone production.
醛固酮瘤（APA）是最常见的可治愈的高血压病因。大多数 APA 都具有离子通道或转运蛋白功能获得性体细胞突变。在此，我们报告了神经元细胞黏附基因 CADM1 突变的发现、复制和表型。对 40 个和 81 个 APA 的独立全外显子组测序发现，两名患者的高血压和周期性原发性醛固酮增多症经肾上腺切除术治愈，他们的 CADM1 基因在跨膜区存在 p.Val380Asp 或 p.Gly379Asp 变异。重复实验鉴定出另外两例各带有一个变异的 APA（总计，n=6）。与野生型相比，在转染突变体的人肾上腺皮质 H295R 细胞中，基因表达谱中上调最显著的基因（10-25 倍）是 CYP11B2（醛固酮合酶），且生物节律是差异表达最显著的过程。CADM1 敲低或突变抑制了缝隙连接（GJ）通透性染料转移。GJ 阻滞剂 Gap27 对 CYP11B2 的作用类似于 CADM1 突变。人肾上腺球状带（ZG）的 GJA1（主要 GJ 蛋白）表达呈斑片状，且 CYP11B2 阳性微结节中环形 GJ（GJ 通讯的后遗症）比相邻 ZG 中不那么突出。CADM1 的体细胞突变可导致可逆性高血压，并揭示了 GJ 通讯在抑制生理性醛固酮产生中的作用。
