Journal Article

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

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

2024

Overview

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. Short tandem repeat mutations in a primate Alu element on chromosome 15q cause activation of a thyroid-specific enhancer, upregulating MIR7-2 / MIR1179 . This results in defective thyroid proliferation and thyrotropin resistance.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 692/308/2056 / 692/699/2743/1841 / Agriculture / Animal Genetics and Genomics / Animals / Biomedical and Life Sciences / Biomedicine / Cancer Research / Chromatin / Chromosome 15 / Chromosomes / Chromosomes, Human, Pair 15 - genetics / Enhancer Elements, Genetic / Female / Gene Function / Genomes / Genotype & phenotype / Haplotypes / Human Genetics / Humans / Male / MicroRNAs / MicroRNAs - genetics / Microsatellite Repeats - genetics / miRNA / Monkeys & apes / Mutation / Pedigree / Pituitary / Primates - genetics / Thyrocytes / Thyroid / Thyroid gland / Thyroid Gland - metabolism / Thyroid-stimulating hormone / Thyrotropin - genetics