Kcne2 deletion uncovers its crucial role in thyroid hormone biosynthesis.
Kcne2 deletion uncovers its crucial role in thyroid hormone biosynthesis.
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作者：
甲状腺功能障碍影响全世界1-4%的人口，导致包括神经发育障碍、侏儒症和心律失常在内的缺陷。在这里，我们表明，KCNQ 1和KCNE 2形成一个TSH刺激的，组成型活性，甲状腺细胞钾离子通道所需的正常甲状腺激素的生物合成。靶向破坏Kcne 2可使甲状腺碘蓄积受损达8倍，使母乳排出受损，使乳汁T4含量减半，导致甲状腺功能减退、窝仔数减少50%、侏儒症、脱发、甲状腺肿和心脏异常，包括肥大、纤维化和缩短分数减少。通过对幼仔给予T3/T4、在产前和产后向母鼠补充T4或在断奶前用Kcne 2 +/+母鼠代孕，可缓解脱毛、侏儒症和心脏异常;相反，通过用Kcne 2 −/−母鼠代孕，可在Kcne 2 +/+幼仔中引发这些症状。这些数据确定了一个关键的甲状腺细胞K+通道，为甲状腺疾病提供了一种可能的新的治疗途径，并预测了一些先前确定的KCNE 2和KCNQ 1相关的人类心律失常的内分泌成分。
Thyroid dysfunction affects 1–4% of the population worldwide, causing defects including neurodevelopmental disorders, dwarfism and cardiac arrhythmia. Here, we show that KCNQ1 and KCNE2 form a TSH-stimulated, constitutively-active, thyrocyte K+ channel required for normal thyroid hormone biosynthesis. Targeted disruption of Kcne2 impaired thyroid iodide accumulation up to 8-fold, impaired maternal milk ejection and halved milk T4 content, causing hypothyroidism, 50% reduced litter size, dwarfism, alopecia, goiter, and cardiac abnormalities including hypertrophy, fibrosis, and reduced fractional shortening. The alopecia, dwarfism and cardiac abnormalities were alleviated by T3/T4 administration to pups, by supplementing dams with T4 pre- and postpartum, or by pre-weaning surrogacy with Kcne2+/+ dams; conversely these symptoms were elicited in Kcne2+/+ pups by surrogacy with Kcne2−/− dams. The data identify a critical thyrocyte K+ channel, provide a possible novel therapeutic avenue for thyroid disorders, and predict an endocrine component to some previously-identified KCNE2- and KCNQ1-linked human cardiac arrhythmias.
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影响因子：
2.8
作者：
FORFAR, JC;MILLER, HC;TOFT, AD
通讯作者：
TOFT, AD
DOI：
10.2190/adly-1uu0-1a8l-hpxy
发表时间：
1990-01-01
影响因子：
2
作者：
HAGGERTY, JJ;GARBUTT, JC;NEMEROFF, CB
通讯作者：
NEMEROFF, CB
影响因子：
39.2
作者：
Hak, AE;Pols, HAP;Witteman, JCM
通讯作者：
Witteman, JCM
影响因子：
4.8
作者：
FUKUDA, H;OHSHIMA, K;GREER, MA
通讯作者：
GREER, MA
影响因子：
5.9
作者：
GAVIN, LA
通讯作者：
GAVIN, LA