6398 Activating Mutations in a Primate-Specific Enhancer of MIR7-2/MIR1179 Are a Common Cause of Resistance to Thyrotropin
Authors: Grasberger Helmut , Dumitrescu Alexandra , Liao Xiao-Hui , Swanson Elliott , Weiss Roy E , Srichomkwun Panudda , Pappa Theodora , Chen Junfeng , Yoshimura Takashi , Hoffmann Phillip , Franca Monica Malheiros , Onigata Kazumichi , Costagliola Sabine , Ranchalis Jane , Vollger Mitchell R , Stergachis Andrew B , Chong Jessica X , Bamshad Michael J , Smits Guillaume , Vassart Gilbert , Refetoff Samuel 
Published: October 2024

Disclosure: H. Grasberger: None. A. Dumitrescu: None. X. Liao: None. E. Swanson: None. R.E. Weiss: None. P. Srichomkwun: None. T. Pappa: None. J. Chen: None. T. Yoshimura: None. P. Hoffmann: None. M. Franca: None. K. Onigata: None. S. Costagliola: None. J. Ranchalis: None. M.R. Vollger: None. A.B. Stergachis: None. J.X. Chong: None. M.J. Bamshad: None. G. Smits: None. G. Vassart: None. S. Refetoff: None.

We previously identified a novel form of dominantly inherited resistance to TSH (RTSH), without TSH or TSH receptor mutations, that was linked to a locus on chromosome 15q (Grasberger et al., Hum. Genet. 2005). At birth, affected individuals present with nongoitrous euthyroid hyperthyrotropinemia that persists into adulthood and is frequently associated with high serum thyroglobulin levels not correlated with the degree of TSH elevation. Using whole genome sequencing we now report that noncoding mutations in an intergenic (TTTG)4 short tandem repeat (STR) underlie this form of RTSH in all 82 affected subjects from 12 unrelated families of different ethnic origins. Affected were heterozygous for the deletion of one repeat unit (10 families), or a single nucleotide change within the STR (two families). The STR maps to a primate-specific retrotransposon (AluSx1) with weak thyroid-specific enhancer-like chromatin signature. Paradoxically, some affected individuals appear prone to manifest proliferative thyroid disease since three of the affected subjects in our cohort required thyroidectomy for large nodular goiters in middle age. To investigate the consequence of these noncoding mutations we performed single-molecule chromatin fiber sequencing (Fiber-seq) and RNA-seq on thyroid specimens from subjects representing the two different mutations, and control thyroid tissues (healthy and nontoxic multinodular goiter) without STR mutation. Studies revealed that the mutant STRs stabilize transcription factor (TF) occupancy over the STR site, altering the spacing of adjacent FOXE1 binding elements. Increased TF occupancy at the mutated STR site actuates a complete enhancer cluster that selectively upregulates a bicistronic micro-RNA locus 35 kb downstream. The miRNA primary transcript is specifically overexpressed from the mutant STR allele leading to marked overexpression of the mature miRNA products, MIR7-5P and MIR1179. This was not observed in primary skin fibroblasts from RTSH subjects, consistent with thyroid specific regulation of the enhancer and lack of an extrathyroidal phenotype. An imbalance in signaling pathways targeted by MIR7-5P provides a working model for this novel cause of RTSH. These findings broaden our current knowledge of genetic defects altering pituitary-thyroid feedback regulation and highlight the function of this locus as primate-specific modulator of thyroid function.

Presentation: 6/1/2024