Fibrous dysplasia/McCune-Albright syndrome: state-of-the-art advances, pathogenesis, and basic/translational research

Fibrous dysplasia/McCune-Albright syndrome: state-of-the-art advances, pathogenesis, and basic/translational research

Abstract Fibrous dysplasia/McCune Albright syndrome (FD/MAS) is a rare genetic disease caused by postzygotic activating variants in the GNAS gene, encoding the α subunit of stimulatory G protein (Gαs). Although multiple organs may be involved, skeletal lesions usually represent the most severe and l...

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Main Authors: Biagio Palmisano, Camryn Berry, Alison Boyce, Julia F. Charles, Michael T. Collins, Alessandro Corsi, Fernando A. Fierro, Anne-Marie Heegaard, Hanne van der Heijden, Charles S. Hoffman, Chelsea Hopkins, Jaymin Upadhyay, Paul M. Wehn, Kelly L. Wentworth, Yingzi Yang, Xuefeng Zhao, Edward C. Hsiao, Mara Riminucci
Format: Article
Language:English
Published: BMC 2025-08-01
Series:Orphanet Journal of Rare Diseases
Subjects:
GNAS
Rare disease
Skeletal stem cell
Mouse models
Bone remodeling
Osteoclastogenesis
Online Access:https://doi.org/10.1186/s13023-025-03909-8
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Summary:Abstract Fibrous dysplasia/McCune Albright syndrome (FD/MAS) is a rare genetic disease caused by postzygotic activating variants in the GNAS gene, encoding the α subunit of stimulatory G protein (Gαs). Although multiple organs may be involved, skeletal lesions usually represent the most severe and least treatable expression of the disease, leading to bone deformities, spontaneous fractures, and chronic pain that severely reduce patients’ quality of life. The recognition of the causative Gαs variants and the consequent ligand-independent activation of the adenylyl cyclase/cAMP/PKA pathway has provided a clear molecular explanation to most extra-skeletal pathologies of FD/MAS, leading to the development of effective therapeutic approaches. In contrast, a detailed understanding of the cellular and molecular mechanisms that act downstream of the Gαs pathway to generate FD bone lesions and clinical expression thereof remain elusive. Multiple key issues remain to be addressed, including some questions that have recently emerged such as the interaction between mutated and non-mutated cells and the role of the latter in the development of the fibrotic tissue. In this review, we provide a summary of the proof-of-concept, preclinical data, and experimental tools that have emerged to date from basic and translational studies on FD and represent the background for future research on the pathogenesis and treatment of this rare disease.
ISSN:1750-1172

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