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Updated: Jun 27, 2025

Spontaneous Murine Model of Anaplastic Thyroid Cancer
Published on: February 3, 2023
STR mutations on chromosome 15q cause thyrotropin resistance by activating a primate-specific enhancer of
Helmut Grasberger1, Alexandra M Dumitrescu2,3, Xiao-Hui Liao2
1Department of Internal Medicine, Medical School, University of Michigan, Ann Arbor, MI, USA.
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 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.
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