# Molecular definition of pseudohypoparathyroidism

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $66,034

## Abstract

ABSTRACT
 Pseudohypoparathyroidism type Ib (PHP1B), a rare imprinting disorder, is caused by loss-of-
methylation at one or several differentially methylation regions (DMR) on the maternal GNAS allele
thereby reducing expression of the simulatory G protein (Gαs). Besides PTH-resistant hypocalcemia
and hyperphosphatemia, additional clinical and laboratory abnormalities are being recognized with
increasing frequency. Thus, considerable overlap has become apparent between PHP1B and PHP1A.
In fact, we encountered several PHP1B patients, who were evaluated for hyperphagia leading to early-
onset obesity many years before a GNAS-related disorder was considered and before PTH-resistance
had developed. Autosomal dominant PHP1B (AD-PHP1B) is caused by deletions in GNAS or STX16,
but the majority of these patients are sporadic and with the exception of few cases caused by paternal
uniparental isodisomy/heterodisomy, the genetic defect(s) leading to this disease variant remains
unknown. A novel maternally inherited GNAS deletion that is associated with broad methylation
changes at this locus was recently discovered, althought the patient had no family history of the
disease; this raises the possibility that other “sporadic” PHP1B cases are also caused by as-yet
undefined GNAS/STX16 mutations. Through whole genome sequencing (WGS), we furthermore
identified a large GNAS inversion in a new AD-PHP1B kindred, which causes loss-of-methylation at
GNAS exon A/B alone. When this inversion is located on the paternal allele, no functional XLαs (extra-
large variants of Gαs) can be generated, which is likely to lead to failure-to-thrive and short stature, i.e.
findings similar to those observed in humans or rodents with XLαs-deficiency. We now plan to
determine whether genetic and epigenetic GNAS changes are a frequent cause of early-onset obesity,
congenital hypothyroidism, and potentially short stature, and whether these abnormalities can be
encountered even in the absence of PTH-resistant hypocalcemia (Aim 1). To determine whether
disease-causing mutations in GNAS/STX16 lead to epigenetic GNAS changes when introduced in vitro,
we developed cell lines from the stromal vascular fraction (SVF) of brown adipose tissue in which
deletions were introduced through CRISPR/Cas9. We will determine whether these cellular
manipulations change allele-specific GNAS methylation and/or parent-specific expression of Gαs and
its splice variants, and thus the response to hormonal stimulation (Aim 2). We will furthermore search in
new AD-PHP1B families with GNAS methylation changes, but without mutations at known disease-
causing sites, for novel GNAS/STX16 deletions/inversions, and we will determine through WGS,
whether adult females with “sporadic” PHP1B, who have healthy children without epigenetic GNAS
changes, could be affected an autosomal recessive disease variant (Aim 3).

## Key facts

- **NIH application ID:** 10099745
- **Project number:** 3R01DK046718-26S1
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** HARALD W. JUEPPNER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $66,034
- **Award type:** 3
- **Project period:** 1993-05-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10099745

## Citation

> US National Institutes of Health, RePORTER application 10099745, Molecular definition of pseudohypoparathyroidism (3R01DK046718-26S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10099745. Licensed CC0.

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