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

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

doi:10.1038/s41588-024-01717-7

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

Nat Genet. 2024 May;56(5):877-888. doi: 10.1038/s41588-024-01717-7. Epub 2024 May 7.

Authors

Helmut Grasberger¹, Alexandra M Dumitrescu^{2

3}, Xiao-Hui Liao², Elliott G Swanson^{4

5}, Roy E Weiss⁶, Panudda Srichomkwun², Theodora Pappa², Junfeng Chen⁷, Takashi Yoshimura⁷, Phillip Hoffmann⁸, Monica Malheiros França², Rebecca Tagett⁹, Kazumichi Onigata², Sabine Costagliola¹⁰, Jane Ranchalis⁴, Mitchell R Vollger⁴, Andrew B Stergachis^{4

5

11}, Jessica X Chong^{4

11}, Michael J Bamshad^{4

5

11}, Guillaume Smits^{8

12}, Gilbert Vassart¹⁰, Samuel Refetoff^{13

14

15}

Affiliations

¹ Department of Internal Medicine, Medical School, University of Michigan, Ann Arbor, MI, USA.
² Department of Medicine, The University of Chicago, Chicago, IL, USA.
³ Committee on Molecular Metabolism and Nutrition, The University of Chicago, Chicago, IL, USA.
⁴ Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA.
⁵ Department of Genome Sciences, University of Washington, Seattle, WA, USA.
⁶ Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA.
⁷ Institute of Transformative Bio-Molecules (WPI-ITbM) and Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Japan.
⁸ Interuniversity Institute of Bioinformatics in Brussels, Université Libre de Bruxelles-Vrije Universiteit Brussel, Brussels, Belgium.
⁹ Michigan Medicine BRCF Bioinformatics Core, University of Michigan, Ann Arbor, MI, USA.
¹⁰ Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Université Libre de Bruxelles, Brussels, Belgium.
¹¹ Brotman-Baty Institute for Precision Medicine, Seattle, WA, USA.
¹² Center of Human Genetics, Hôpital Erasme, Hôpital Universitaire de Bruxelles, and Department of Genetics, Hôpital Universitaire des Enfants Reine Fabiola, Hôpital Universitaire de Bruxelles, Université Libre de Bruxelles, Brussels, Belgium.
¹³ Department of Medicine, The University of Chicago, Chicago, IL, USA. refetoff@uchicago.edu.
¹⁴ Committee on Genetics, The University of Chicago, Chicago, IL, USA. refetoff@uchicago.edu.
¹⁵ Department of Pediatrics, The University of Chicago, Chicago, IL, USA. refetoff@uchicago.edu.

PMID: 38714869
DOI: 10.1038/s41588-024-01717-7

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.

MeSH terms

Animals
Chromosomes, Human, Pair 15* / genetics
Enhancer Elements, Genetic*
Female
Humans
Male
MicroRNAs* / genetics
Microsatellite Repeats* / genetics
Mutation*
Pedigree
Primates / genetics
Thyroid Gland / metabolism
Thyrotropin* / genetics