| Authors |
Iwasaki Y, Bastepe M
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| Submitted By |
MURAT BASTEPE on 11/6/2025 |
| Status |
Published |
| Journal |
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research |
| Year |
2025 |
| Date Published |
10/28/2025 |
| Volume : Pages |
40 : 1207 - 1217 |
| PubMed Reference |
40972900 |
| Abstract |
Pseudohypoparathyroidism (PHP) was first described as a syndrome characterized
by PTH resistance combined with skeletal abnormalities known as Albright's
hereditary osteodystrophy (AHO). Studies have since focused on genetic or
epigenetic alterations underlying PHP and related disorders. The a-subunit of
the stimulatory G protein (Gsa) mediates the signaling of G protein-coupled
receptors that stimulate cAMP generation. The Gsa-cAMP cascade is pivotal for
human skeletal growth, as evidenced by pathogenic mutations converging on this
signaling pathway in a spectrum of skeletal dysplasias that overlap with AHO.
The gene encoding Gsa, GNAS, is subject to genomic imprinting, an epigenetic
mechanism governing allele-specific gene expression through differential
methylation. Parental allele contribution to Gsa expression differs among
tissues. While Gsa is biallelically transcribed in most tissues, including bone
and cartilage, the paternal Gsa allele is suppressed in a limited number of
cells/tissues, including the proximal renal tubule, where PTH exerts critical
actions. Therefore, Gsa mutations cause distinct clinical manifestations
according to the affected parental allele. While maternal mutations result in
PHP type 1A, which consists of PTH resistance and AHO, paternal mutations lead
to pseudo-pseudohypoparathyroidism (PPHP), that is, AHO without hormone
resistance. Epigenetic alterations of GNAS cause PHP type 1B (PHP1B), defined by
PTH resistance in the absence of AHO. Thus, genomic imprinting plays a key role
in the phenotypes associated with GNAS alterations. Investigations on the
genetic cause of PHP1B have identified crucial imprinting control regions of
GNAS, whose functions were elucidated only recently using human embryonic stem
cells to model imprinting regulatory mechanisms in the early embryo. We herein
review the current understanding of the genetic and epigenetic basis of PHP and
related disorders, focusing on their skeletal manifestations.,
Pseudohypoparathyroidism (PHP) is characterized by PTH resistance with skeletal
and developmental abnormalities. Pseudohypoparathyroidism results from genetic
or epigenetic alterations affecting the GNAS gene. GNAS encodes the stimulatory
G protein a-subunit, a signaling mediator essential for human skeletal growth.
GNAS undergoes genomic imprinting, that is, transcriptional regulation occurs
differently on each parental allele. This epigenetic mechanism plays a key role
in the phenotypes of PHP and related disorders. Recent studies have elucidated
the molecular basis of GNAS imprinting, revealing the mechanisms that operate
during early embryonic stages. Such advances enabled a logical approach to the
molecular diagnosis of PHP.
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