# Molecular definition of pseudohypoparathyroidism

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2021 · $422,252

## Abstract

ABSTRACT
 Pseudohypoparathyroidism type Ib (PHP1B), a rare disorder, is caused by abnormal
imprinting of differentially methylated regions (DMR) on the maternal GNAS allele during oocyte
maturation, thereby reducing expression of the α-subunit of the stimulatory G protein (Gαs).
Autosomal dominant PHP1B (AD-PHP1B) variants can be caused either by deletions, inversions,
or duplications within the STX16/GNAS locus, but most PHP1B patients are sporadic
(sporPHP1B) and their molecular defects remain unresolved, except for those cases affected by
paternal uniparental disomy (patUPD20q). PTH-resistant hypocalcemia and hyperphosphatemia
is the most prominent laboratory abnormality in PHP1B, but resistance to other hormones and
additional aspects of this disease are now well recognized. To identify the molecular causes
underlying different PHP1B variants, each with unique epigenetic changes, we will investigate
patients with as-yet undefined genetic defects. In Aim 1, we will use various approaches,
including comparative genomic hybridization (CGH), whole genome sequencing (WGS), and
genetic linkage studies, to search in familial and sporadic forms of PHP1B with loss-of-
methylation (LOM) at exon A/B alone (PHP1BA/B-) for GNAS duplications and novel mutations
within STX16/GNAS or elsewhere in the genome. In addition, we will search for a novel genetic
defect(s) outside the chromosome 20q13.3 region that leads to a familial PHP1B variant
characterized by LOM at the maternal GNAS exons A/B, XL, and AS, yet gain-of-methylation
(GOM) of the maternal exon NESP (PHP1BNESP+), i.e. epigenetic findings indistinguishable from
those in sporPHP1B patients. In addition, we will define previously not recognized clinical
features of PHP1B, namely reduced female fertility and a high incidence of PHP1B associated
with in vitro fertilization (IVF). Furthermore, we will expand our observation that female carriers of
a STX16/GNAS mutation preferentially pass the mutant allele to the next generation. In Aim 2,
we will determine whether genomic deletions spanning the region from Stx16 to Gnas that were
introduced into mice through iGONAD allow the rapid identification of regions responsible for
Gnas methylation. These efforts are expected to generate a viable murine model of AD-PHP1B
that will help determine which molecular mechanisms contribute to development of PTH-resistant
hypocalcemia and hyperphosphatemia, and which Gnas-derived transcripts affect methylation of
the DMRs at exons Nesp and 1A during oocyte maturation. Lastly, we will use re-primed naïve
H9 embryonic stem cells and iPS cells derived from an AD-PHP1B patient to determine whether
AS transcripts regulate methylation of GNAS exons NESP and A/B.

## Key facts

- **NIH application ID:** 10299199
- **Project number:** 2R01DK046718-28
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** HARALD W. JUEPPNER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $422,252
- **Award type:** 2
- **Project period:** 1993-05-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10299199

## Citation

> US National Institutes of Health, RePORTER application 10299199, Molecular definition of pseudohypoparathyroidism (2R01DK046718-28). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10299199. Licensed CC0.

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