| Autor: |
Grasberger, Helmut, Dumitrescu, Alexandra M., Liao, Xiao-Hui, Swanson, Elliott G., Weiss, Roy E., Srichomkwun, Panudda, Pappa, Theodora, Chen, Junfeng, Yoshimura, Takashi, Hoffmann, Phillip, França, 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 |
| Zdroj: |
Nature Genetics; 20240101, Issue: Preprints p1-12, 12p |
| Abstrakt: |
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)4short tandem repeat (STR) underlie dominantly inherited RTSH in all 82 affected participants from 12 unrelated families. The STR is contained in a primate-specific Aluretrotransposon 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/MIR1179locus 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. |
| Databáze: |
Supplemental Index |
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