英国伦敦玛丽女王大学Morris J. Brown和Elena A. B. Azizan共同合作，近期取得重要工作进展。他们研究发现了醛固酮生成腺瘤中CADM1的体细胞突变和醛固酮产生的间隙连接依赖性调控。相关研究成果2023年6月8日在线发表于《自然—遗传学》杂志上。

据介绍，产生醛固酮的腺瘤 (APA) 是最常见的可治愈的高血压病因。 大多数具有离子通道或转运蛋白的功能获得性体细胞突变。

研究人员报道了神经元细胞粘附基因CADM1突变的发现、复制和表型。对40和81个APA的独立全外显子组测序发现，在两名通过肾上腺切除术治愈高血压和周期性原发性醛固酮增多症的患者中，存在膜内p.Val380Asp或p.Gly379Asp变体。复制为每个变体确定了另外两个APA（总共，n=6） 。在用突变转导的人类肾上腺皮质H295R细胞中（与野生型相比）上调最多的基因（10至25倍）是CYP11B2（醛固酮合成酶），生物节律是差异表达最多的过程。CADM1敲低或突变抑制间隙连接（GJ）-可渗透染料转移。Gap27阻断GJ使CYP11B2增加，类似于CADM1突变。人肾上腺肾小球带（ZG）GJA1（主要GJ蛋白）的表达呈斑片状，环状GJs（GJ通讯的后遗症）在CYP11B2阳性微模块中的表达不如相邻的ZG突出。

总之，这一研究表明，CADM1的体细胞突变导致可逆性高血压，并揭示了GJ通讯在抑制生理性醛固酮产生中的作用。

附：英文原文

Title: Somatic mutations of CADM1 in aldosterone-producing adenomas and gap junction-dependent regulation of aldosterone production

Author: Wu, Xilin, Azizan, Elena A. B., Goodchild, Emily, Garg, Sumedha, Hagiyama, Man, Cabrera, Claudia P., Fernandes-Rosa, Fabio L., Boulkroun, Sheerazed, Kuan, Jyn Ling, Tiang, Zenia, David, Alessia, Murakami, Masanori, Mein, Charles A., Wozniak, Eva, Zhao, Wanfeng, Marker, Alison, Buss, Folma, Saleeb, Rebecca S., Salsbury, Jackie, Tezuka, Yuta, Satoh, Fumitoshi, Oki, Kenji, Udager, Aaron M., Cohen, Debbie L., Wachtel, Heather, King, Peter J., Drake, William M., Gurnell, Mark, Ceral, Jiri, Ryska, Ales, Mustangin, Muaatamarulain, Wong, Yin Ping, Tan, Geok Chin, Solar, Miroslav, Reincke, Martin, Rainey, William E., Foo, Roger S., Takaoka, Yutaka, Murray, Sandra A., Zennaro, Maria-Christina, Beuschlein, Felix, Ito, Akihiko, Brown, Morris J.

Issue&Volume: 2023-06-08

Abstract: 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.

DOI: 10.1038/s41588-023-01403-0

Source: https://www.nature.com/articles/s41588-023-01403-0