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Current Osteoporosis Reports

, Volume 13, Issue 3, pp 146–158 | Cite as

GNAS Spectrum of Disorders

  • Serap Turan
  • Murat BastepeEmail author
Rare Bone Disease (CB Langman and E Shore, Section Editors)
Part of the following topical collections:
  1. Topical Collection on Rare Bone Diseases

Abstract

The GNAS complex locus encodes the alpha-subunit of the stimulatory G protein (Gsα), a ubiquitous signaling protein mediating the actions of many hormones, neurotransmitters, and paracrine/autocrine factors via generation of the second messenger cAMP. GNAS gives rise to other gene products, most of which exhibit exclusively monoallelic expression. In contrast, Gsα is expressed biallelically in most tissues; however, paternal Gsα expression is silenced in a small number of tissues through as-yet-poorly understood mechanisms that involve differential methylation within GNAS. Gsα-coding GNAS mutations that lead to diminished Gsα expression and/or function result in Albright’s hereditary osteodystrophy (AHO) with or without hormone resistance, i.e., pseudohypoparathyroidism type-Ia/Ic and pseudo-pseudohypoparathyroidism, respectively. Microdeletions that alter GNAS methylation and, thereby, diminish Gsα expression in tissues in which the paternal Gsα allele is normally silenced also cause hormone resistance, which occurs typically in the absence of AHO, a disorder termed pseudohypoparathyroidism type-Ib. Mutations of GNAS that cause constitutive Gsα signaling are found in patients with McCune-Albright syndrome, fibrous dysplasia of bone, and different endocrine and non-endocrine tumors. Clinical features of these diseases depend significantly on the parental allelic origin of the GNAS mutation, reflecting the tissue-specific paternal Gsα silencing. In this article, we review the pathogenesis and the phenotypes of these human diseases.

Keywords

GNAS Pseudohypoparathyroidism Gsα Alpha-subunit of the stimulatory G protein 

Notes

Acknowledgments

The studies conducted in the laboratory of M.B. are funded in part by research grants from the National Institute of Diabetes and Digestive and Kidney Diseases (RO1 DK073911), the March of Dimes Foundation, and the Milton Fund.

Compliance with Ethics Guidelines

Conflict of Interest

S Turan and M Bastepe both declare no conflicts of interest.

Human and Animal Rights and Informed Consent

All studies by the authors involving animal and/or human subjects were performed after approval by the appropriate institutional review boards. When required, written informed consent was obtained from all participants.

References

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Pediatric EndocrinologyMarmara University School of Medicine HospitalIstanbulTurkey
  2. 2.Endocrine Unit, Department of MedicineMassachusetts General Hospital and Harvard Medical SchoolBostonUSA

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