GNAS gene mutations affecting XLαs and bone health: A long neglected relationship.

Abstract

The GNAS locus is an imprinted site. The α-subunit of the stimulatory G protein (Gsα) and extralarge variant (XLαs) are the two important products of the GNAS locus. The abnormal expression of Gsα is associated with pseudohypoparathyroidism (PHP) and related disorders, including Albright hereditary osteodystrophy (AHO), pseudopseudohypoparathyroidism (PPHP), and progressive osseous heteroplasia (POH). XLαs protein can mimic the catalytic intracellular synthesis of cyclic adenosine monophosphate (cAMP) by Gsα in response to parathyroid hormone (PTH) stimulation, which may be involved in the pathogenesis of PPHP and POH in patients with paternal GNAS defects. A paternally inherited nonsense variant in the first exon of XLαs in an adult patient may be associated with fractures and osteopetrosis. The relationship between the XLαs product of the GNAS locus and bone remodeling may have been overlooked. Here, we summarize the phenotypes of genetic mouse models and clinical cases of XLαs variations and suggest that the abnormal paternal expression of XLαs may be associated with the development of POH and affect osteoblast and osteoclast differentiation.

• Authors: Yanni Xie, Xiang Chen, Ying Xie, Xijie Yu
• Journal: Clinical genetics (Clin Genet) Vol. 104 Issue 3 Pg. 279-286 (09 2023) ISSN: 1399-0004 [Electronic] Denmark
• PMID: 37249323 (Publication Type: Journal Article, Review, Research Support, Non-U.S. Gov't)
• Copyright: © 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Chemical References

• 5-phenylpent-4-enyl-1-hydroperoxide
• Chromogranins
• GTP-Binding Protein alpha Subunits, Gs
• GNAS protein, human

Topics

• Humans
• Animals
• Mice
• Bone Density
• Chromogranins (genetics)
• GTP-Binding Protein alpha Subunits, Gs (genetics)
• Pseudohypoparathyroidism (genetics)
• Mutation (genetics)