美国芝加哥大学Samuel Refetoff课题组的研究发现，15q染色体上的STR突变通过激活灵长类动物特异性MIR7-2/MIR1179增强子导致促甲状腺激素（TSH）抵抗。2024年5月7日，国际学术期刊《自然-遗传学》发表了这一成果。

研究人员在12个非亲缘关系家庭的82名受影响者中发现，(TTTG)4短串联重复（STR）的非编码突变是显性RTSH的遗传基础。该STR位于一个具有甲状腺特异性顺式调控染色质特征的灵长类特异性Alu反转座子中。纤维-序列和RNA-序列研究表明，突变的STR激活了甲状腺特异性增强子群，导致下游35kb处的双螺旋MIR7-2/MIR1179单倍型基因座特异性上调，其microRNA产物在参与者的甲状腺细胞中过表达。

这些微RNA靶向信号通路的失衡为RTSH的病因提供了一个研究模型。这一发现拓宽了人们对垂体-甲状腺反馈调节基因缺陷的认识。

据介绍，TSH是甲状腺生长和功能的主要调节因子。TSH抵抗（RTSH）是指对TSH的敏感性降低。RTSH的显性遗传与15q染色体上的一个基因座有关，但其遗传基础一直不得而知。

附：英文原文

Title: STR mutations on chromosome 15q cause thyrotropin resistance by activating a primate-specific enhancer of MIR7-2/MIR1179

Author: Grasberger, Helmut, Dumitrescu, Alexandra M., Liao, Xiao-Hui, Swanson, Elliott G., Weiss, Roy E., Srichomkwun, Panudda, Pappa, Theodora, Chen, Junfeng, Yoshimura, Takashi, Hoffmann, Phillip, Frana, Monica Malheiros, Tagett, Rebecca, Onigata, Kazumichi, Costagliola, Sabine, Ranchalis, Jane, Vollger, Mitchell R., Stergachis, Andrew B., Chong, Jessica X., Bamshad, Michael J., Smits, Guillaume, Vassart, Gilbert, Refetoff, Samuel

Issue&Volume: 2024-05-07

Abstract: Thyrotropin (TSH) is the master regulator of thyroid gland growth and function. Resistance to TSH (RTSH) describes conditions with reduced sensitivity to TSH. Dominantly inherited RTSH has been linked to a locus on chromosome 15q, but its genetic basis has remained elusive. Here we show that non-coding mutations in a (TTTG)4 short tandem repeat (STR) underlie dominantly inherited RTSH in all 82 affected participants from 12 unrelated families. The STR is contained in a primate-specific Alu retrotransposon with thyroid-specific cis-regulatory chromatin features. Fiber-seq and RNA-seq studies revealed that the mutant STR activates a thyroid-specific enhancer cluster, leading to haplotype-specific upregulation of the bicistronic MIR7-2/MIR1179 locus 35kb downstream and overexpression of its microRNA products in the participants’ thyrocytes. An imbalance in signaling pathways targeted by these micro-RNAs provides a working model for this cause of RTSH. This finding broadens our current knowledge of genetic defects altering pituitary–thyroid feedback regulation.

DOI: 10.1038/s41588-024-01717-7

Source: https://www.nature.com/articles/s41588-024-01717-7