Nishihara Eijun, Fukata Shuji, Hirokawa Mitsuyoshi, Higuchi Miyoko, Ito Mitsuru, Nishikawa Mitsushige, Miyauchi Akira, Matsuse Michiko, Mitsutake Norisato, Ito Yuka, Hishinuma Akira, Kogai Takahiko, Akamizu Takashi
Center for Excellence in Thyroid Care, Kuma Hospital, Kobe 650-0011, Japan.
Department of Radiation Medical Sciences, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki 852-8523, Japan.
J Clin Endocrinol Metab. 2025 Mar 17;110(4):973-982. doi: 10.1210/clinem/dgae699.
Kelch-like ECH-associated protein 1 (KEAP1) is associated with nuclear factor erythroid-2-related factor 2 (NRF2) and promotes NRF2 degradation in normal conditions. Genetic abnormality in KEAP1 is a rare disease and presents with familial multinodular goiter.
This study assessed the clinical and molecular findings concerning nodular formation in the thyroid gland of patients harboring KEAP1 germline mutations.
Next-generation sequencing analysis targeting goiter-associated genes was performed on 39 patients with familial multinodular goiter. The expression of NRF2-targeted genes from surgical thyroid specimens of patients with KEAP1 mutations were analyzed using a whole-transcript expression array and immunohistochemistry.
We found 5 probands with pathogenic heterozygous mutations in KEAP1 (p.Q86*, p.L136P, p.V411fs, p.R415C, and p.R483H) that had no meaningful concomitance with mutations of other goiter-associated genes at germline and somatic levels. Their common histopathological features showed multinodular goiters in the entire thyroid gland with few degenerative lesions or complications of malignancy and slow proliferation indicating less than 1% at the Ki-67 labeling index. Among 42 NRF2-targeted genes, antioxidant genes were most frequently upregulated (11/12) in the nodule, followed by detoxification genes (6/11). Immunohistochemical analysis showed relatively high expression of glutathione peroxidase 2 and NAD(P)H quinone oxidoreductase 1 (representative NRF2-targeted genes) in the nodules of various patients harboring KEAP1 mutations.
KEAP1 germline heterozygous mutations exert excessive NRF2 activity in the thyroid gland and may confer cytoprotective effects even under abundant reactive oxygen species associated with thyroid hormone production, resulting in thyroid hyperplasia with scarce degradation.
Kelch样ECH相关蛋白1（KEAP1）与核因子红细胞2相关因子2（NRF2）相关，并在正常条件下促进NRF2降解。KEAP1基因异常是一种罕见疾病，表现为家族性多结节性甲状腺肿。
本研究评估了携带KEAP1种系突变患者甲状腺结节形成的临床和分子学发现。
对39例家族性多结节性甲状腺肿患者进行了针对甲状腺肿相关基因的二代测序分析。使用全转录本表达阵列和免疫组织化学分析了KEAP1突变患者手术切除的甲状腺标本中NRF2靶向基因的表达。
我们发现5名先证者在KEAP1中存在致病性杂合突变（p.Q86*、p.L136P、p.V411fs、p.R415C和p.R483H），在种系和体细胞水平上与其他甲状腺肿相关基因的突变无明显伴随关系。它们常见的组织病理学特征显示整个甲状腺为多结节性甲状腺肿，几乎没有退行性病变或恶性并发症，增殖缓慢，Ki-67标记指数小于1%。在42个NRF2靶向基因中，抗氧化基因在结节中上调最为频繁（11/12），其次是解毒基因（6/11）。免疫组织化学分析显示，在携带KEAP1突变的不同患者的结节中，谷胱甘肽过氧化物酶2和NAD(P)H醌氧化还原酶1（代表性的NRF2靶向基因）表达相对较高。
KEAP1种系杂合突变在甲状腺中发挥过度的NRF2活性，即使在与甲状腺激素产生相关的大量活性氧存在的情况下，也可能赋予细胞保护作用，导致甲状腺增生且降解稀少。
