Department of Internal Medicine, Medical School, University of Michigan, Ann Arbor, MI, USA.
Department of Medicine, The University of Chicago, Chicago, IL, USA.
Nat Genet. 2024 May;56(5):877-888. doi: 10.1038/s41588-024-01717-7. Epub 2024 May 7.
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) 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.
促甲状腺激素（TSH）是甲状腺生长和功能的主要调节因子。对 TSH 的抵抗（RTSH）描述了对 TSH 敏感性降低的情况。显性遗传的 RTSH 与 15q 染色体上的一个基因座有关，但它的遗传基础仍然难以捉摸。在这里，我们显示在 12 个无关家庭的 82 名受影响参与者中，（TTTG）短串联重复（STR）中的非编码突变是显性遗传 RTSH 的基础。该 STR 包含在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 反转录转座子中。纤维测序和 RNA 测序研究表明，突变的 STR 激活了一个甲状腺特异性增强子簇，导致位于 35kb 下游的双顺反子 MIR7-2/MIR1179 基因座的单体特异性上调，并导致参与者甲状腺细胞中其 microRNA 产物的过度表达。这些 microRNAs 靶向的信号通路失衡为 RTSH 的这一病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。
