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STR mutations on chromosome 15q cause thyrotropin resistance by activating a primate-specific enhancer of MIR7-2/MIR1179.
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.
Affiliation
  • Grasberger H; Department of Internal Medicine, Medical School, University of Michigan, Ann Arbor, MI, USA.
  • Dumitrescu AM; Department of Medicine, The University of Chicago, Chicago, IL, USA.
  • Liao XH; Committee on Molecular Metabolism and Nutrition, The University of Chicago, Chicago, IL, USA.
  • Swanson EG; Department of Medicine, The University of Chicago, Chicago, IL, USA.
  • Weiss RE; Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA.
  • Srichomkwun P; Department of Genome Sciences, University of Washington, Seattle, WA, USA.
  • Pappa T; Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA.
  • Chen J; Department of Medicine, The University of Chicago, Chicago, IL, USA.
  • Yoshimura T; Department of Medicine, The University of Chicago, Chicago, IL, USA.
  • Hoffmann P; Institute of Transformative Bio-Molecules (WPI-ITbM) and Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Japan.
  • França MM; Institute of Transformative Bio-Molecules (WPI-ITbM) and Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Japan.
  • Tagett R; Interuniversity Institute of Bioinformatics in Brussels, Université Libre de Bruxelles-Vrije Universiteit Brussel, Brussels, Belgium.
  • Onigata K; Department of Medicine, The University of Chicago, Chicago, IL, USA.
  • Costagliola S; Michigan Medicine BRCF Bioinformatics Core, University of Michigan, Ann Arbor, MI, USA.
  • Ranchalis J; Department of Medicine, The University of Chicago, Chicago, IL, USA.
  • Vollger MR; Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Université Libre de Bruxelles, Brussels, Belgium.
  • Stergachis AB; Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA.
  • Chong JX; Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA.
  • Bamshad MJ; Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA.
  • Smits G; Department of Genome Sciences, University of Washington, Seattle, WA, USA.
  • Vassart G; Brotman-Baty Institute for Precision Medicine, Seattle, WA, USA.
  • Refetoff S; Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA.
Nat Genet ; 56(5): 877-888, 2024 May.
Article in En | MEDLINE | ID: mdl-38714869
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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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Chromosomes, Human, Pair 15 / Thyrotropin / Enhancer Elements, Genetic / Microsatellite Repeats / MicroRNAs / Mutation Limits: Animals / Female / Humans / Male Language: En Journal: Nat Genet Journal subject: GENETICA MEDICA Year: 2024 Document type: Article Affiliation country: Country of publication:
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Chromosomes, Human, Pair 15 / Thyrotropin / Enhancer Elements, Genetic / Microsatellite Repeats / MicroRNAs / Mutation Limits: Animals / Female / Humans / Male Language: En Journal: Nat Genet Journal subject: GENETICA MEDICA Year: 2024 Document type: Article Affiliation country: Country of publication: