# Thyroid Physiology Studies of Inherited Disorders

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2020 · $597,299

## Abstract

PROJECT SUMMARY
The broad objective of this research proposal is to advance our understanding of thyroid physiology through the study of
genetic defects at key regulatory processes. In addition to identification of new syndromes and defects in structural genes,
research centers on regulation of gene expression and epigenetic effects. The program owes its success to the worldwide
referral of patient material, to the clinical and technical skills of the PI's laboratory, and to collaborative arrangements
with accomplished investigators from the US and abroad that provide complementary knowledge and technical expertise.
The proposal encompasses three aims. (1) Discovery of new genes and regulators of gene expression responsible for
congenital and inherited thyroid diseases. Material will be derived from the PI's collection of 4,647 serum and DNA
samples from 1,161 families, of which the genetic defect was identified in only 783 families using the candidate gene
approach. The key cases of the remaining 418 families will be submitted to targeted next-generation sequencing (NGS).
Those that fail to show known thyroid gene defects (approximately 250 familes, based on a pilot study) will be submitted
first to whole exome sequencing and a subgroup without exonic mutations will undergo further whole genome
sequencing. It is anticipated that confirmation of mutations by Sanger sequencing and cosegregation studies, will lead to
the discovery of new genes and/or mechanisms of congenital thyroid disorders. These will be characterized in greater
detail with functional studies and in transgenic mouse models. (2) Acquired resistance to thyroid hormone (RTH) due to
fetal exposure to high thyroid hormone (TH) levels that persists into adulthood will be studied in humans and in mice. In
humans, transmission of this putative epigenetic effect to the next generation (F2) will be studied. In a mouse model, the
precise mechanism of this effect will be determined through biochemical and genetic studies in tissues. Whether RTH
develops in humans after prolonged exposure to high levels of TH during adulthood, will also be determined. (3) The PI
recently identified mutations in a short tandem repeat (STR) in a region of chromosome-15 that results in a dominantly
inherited form of resistance to thyrotropin (RTSH). These mutations manifest with increased expression of two thyroid
specific micro RNAs, as well as an EST (AV707477) downstream from the STR. This region on chromosome-15 is
unique to humans and higher primates. The latter precludes the use of a mouse model for further studies. Thus, a
functional thyroid cell line needs to be identified to allow for probing into the mechanism of this RTSH form using site-
directed mutagenesis. Several alternatives research plans are proposed one of which is the generation of functional WT
and mutant thyroid cell organoids. The latter will be produced from WT and the patients' induced pluripotent stem cells,
derived from their skin fi...

## Key facts

- **NIH application ID:** 9977161
- **Project number:** 5R01DK015070-48
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Samuel Refetoff
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $597,299
- **Award type:** 5
- **Project period:** 1979-07-15 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9977161

## Citation

> US National Institutes of Health, RePORTER application 9977161, Thyroid Physiology Studies of Inherited Disorders (5R01DK015070-48). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9977161. Licensed CC0.

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