# Control of allelic Gsα expression for regulating hormone signaling

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $553,545

## Abstract

Abstract
The α-subunit of the stimulatory G protein (Gsα) mediates the signaling of many hormones, autocrine/paracrine
factors, and neurotransmitters. Gsα and its gene, the GNAS complex locus, are central to many human disorders
with perturbed hormone actions and skeletal development. A distinctive way Gsα signaling is regulated involves
the control of allelic Gsα expression. While Gsα is produced from both parental GNAS alleles in most cells,
including growth plate chondrocytes and osteoblasts, it is derived predominantly from the maternal allele in
specific cells/tissues, most prominently renal proximal tubules and thyroid cells. This monoallelic expression
plays a crucial role in patients with maternal loss-of-function GNAS mutations, causing severe Gsα deficiency
and impaired hormone signaling in those tissues already with monoallelic expression, most prominently affecting
parathyroid hormone (PTH) actions, particularly in the renal proximal tubule, and thyroid-stimulating hormone
(TSH) action in the thyroid. Patients with this disorder, pseudohypoparathyroidism type-1A (PHP1A), also show
additional phenotypes, including brachydactyly and short stature due, at least partly, to Gsα haploinsufficiency
in tissues with normally biallelic Gsα expression. Thus, allelic expression of Gsα critically regulates Gsα signaling
in specific tissues and dictates the phenotypes associated with GNAS mutations. To better understand the
regulation of Gsα-mediated hormone signaling and to develop curative treatments for these diseases, an
improved knowledge of the mechanisms governing allelic Gsα expression is required. We focus on PHP1B, a
pseudohypoparathyroidism subtype characterized by PTH and TSH resistance without the additional
phenotypes in PHP1A. GNAS is a methylated gene, and all patients with PHP1B show maternal hypomethylation
in the GNAS exon A/B differentially methylated region (DMR) adjacent to Gsα-coding exons, suggesting that the
A/B DMR is involved in allelic Gsα expression. However, the role of A/B methylation and the underlying
mechanisms have remained poorly understood. We have recently developed human embryonic stem cell models
of PHP1B by introducing the genetic deletions identified in patients into the GNAS locus. We will employ these
unique tools, as well as induced pluripotent stem cells (iPSCs) derived from healthy and PHP1B patients, to
elucidate the mechanisms by which GNAS methylation regulates allelic Gsα expression. Based on our recently
published findings, we hypothesize that exon A/B methylation, controlled by the upstream NESP55 transcription
in the early embryo, is crucial for allelic Gsα expression and hormone signaling in specific differentiated tissues.
Aim 1 will determine whether inducing NESP55 transcription can increase A/B methylation in cis to rescue Gsα
deficiency due to different GNAS defects. Aim 2 will determine whether the methylation of the GNAS exon A/B
DMR is needed for Gsα expression and hormone signaling in ...

## Key facts

- **NIH application ID:** 10941975
- **Project number:** 1R01DK140244-01
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** MURAT BASTEPE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $553,545
- **Award type:** 1
- **Project period:** 2024-09-02 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10941975

## Citation

> US National Institutes of Health, RePORTER application 10941975, Control of allelic Gsα expression for regulating hormone signaling (1R01DK140244-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10941975. Licensed CC0.

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