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 35 kb 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.

促甲状腺素（TSH）是甲状腺生长和功能的主要调节剂。 TSH 抵抗 (RTSH) 描述了对 TSH 敏感性降低的情况。显性遗传 RTSH 与 15q 染色体上的一个位点有关，但其遗传基础仍然难以捉摸。在这里，我们表明，(TTTG) ₄短串联重复序列 (STR)中的非编码突变是来自 12 个不相关家庭的所有 82 名受影响参与者中显性遗传 RTSH 的基础。 STR 包含在灵长类动物特异性Alu逆转录转座子中，具有甲状腺特异性顺式调节染色质特征。 Fiber-seq 和 RNA-seq 研究表明，突变 STR 激活甲状腺特异性增强子簇，导致下游双顺反子MIR7-2 / MIR1179位点 35 kb 的单倍型特异性上调，并在参与者的甲状腺细胞中过度表达其 microRNA 产物。这些 micro-RNA 所针对的信号通路的不平衡为 RTSH 的这一原因提供了一个工作模型。这一发现拓宽了我们目前对改变垂体-甲状腺反馈调节的遗传缺陷的认识。