Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2018 Apr:109:80-85.
doi: 10.1016/j.bone.2017.09.002. Epub 2017 Sep 6.

GNAS mutations and heterotopic ossification

Murat Bastepe  1
Affiliations
Review

GNAS mutations and heterotopic ossification

Murat Bastepe. Bone. 2018 Apr.

Abstract

GNAS is a complex imprinted gene encoding the alpha-subunit of the stimulatory heterotrimeric G protein (Gsα). GNAS gives rise to additional gene products that exhibit exclusively maternal or paternal expression, such as XLαs, a large variant of Gsα that shows exclusively paternal expression and is partly identical to the latter. Gsα itself is expressed biallelically in most tissues, although the expression occurs predominantly from the maternal allele in a small set of tissues, such as renal proximal tubules. Inactivating mutations in Gsα-coding GNAS exons are responsible for Albright's hereditary osteodystrophy (AHO), which refers to a constellation of physical and developmental disorders including obesity, short stature, brachydactyly, cognitive impairment, and heterotopic ossification. Patients with Gsα mutations can present with AHO in the presence or absence of end-organ resistance to multiple hormones including parathyroid hormone. Maternal Gsα mutations lead to AHO with hormone resistance (i.e. pseudohypoparathyroidism type-Ia), whereas paternal mutations cause AHO alone (i.e. pseudo-pseudohypoparathyroidism). Heterotopic ossification associated with AHO develops through intramembranous bone formation and is limited to dermis and subcutis. In rare cases carrying Gsα mutations, however, ossifications progress into deep connective tissue and skeletal muscle, a disorder termed progressive osseous heteroplasia (POH). Here I briefly review the genetic, clinical, and molecular aspects of these disorders caused by inactivating GNAS mutations, with particular emphasis on heterotopic ossification.

Keywords: GNAS; Heterotopic ossification; Stimulatory G protein; cAMP.

PubMed Disclaimer

Figures

Figure 1
Figure 1. The GNAS complex locus
Located on chromosome 20q13.32 (GRCh38/hg38 chr20:58818918-58911196), GNAS encodes the ubiquitous signaling protein Gsα through the use of exons 1–13. Although Gsα is expressed biallelically in most tissues, paternal Gsα allele is silenced in some tissues (dotted arrow). Additional transcripts include the maternally expressed NESP55 and the paternally expressed XLαs and A/B (also referred to as 1A or 1′). These additional transcripts use individual promoters and first exons that splice onto exons 2–13 of GNAS. GNAS-AS1 transcript is a non-coding transcript derived from the paternal GNAS allele. Boxes and connecting lines depict exons and introns, respectively. Maternal (mat) and paternal (pat) GNAS products are illustrated above and below the gene structure, respectively, and the splicing patterns indicated by dotted curves. “+” indicates the regions of CpG methylation. Arrows indicate direction of transcription.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Weinstein LS, Yu S, Warner DR, Liu J. Endocrine Manifestations of Stimulatory G Protein alpha-Subunit Mutations and the Role of Genomic Imprinting. Endocr Rev. 2001;22:675–705. - PubMed
    1. Bastepe M. The GNAS Locus: Quintessential Complex Gene Encoding Gsalpha, XLalphas, and other Imprinted Transcripts. Curr Genomics. 2007;8:398–414. - PMC - PubMed
    1. Plagge A, Kelsey G, Germain-Lee EL. Physiological functions of the imprinted Gnas locus and its protein variants Galpha(s) and XLalpha(s) in human and mouse. J Endocrinol. 2008;196:193–214. - PubMed
    1. Puzhko S, Goodyer CG, Mohammad AK, Canaff L, Misra M, Jüppner H, Bastepe M, Hendy GN. Parathyroid hormone signaling via Galphas is selectively inhibited by an NH(2) -terminally truncated Galphas: Implications for pseudohypoparathyroidism. J Bone Miner Res. 2011;26:2473–85. - PMC - PubMed
    1. Albright F, Burnett CH, Smith PH, Parson W. Pseudohypoparathyroidism - an example of “Seabright-Bantam syndrome”. Endocrinology. 1942;30:922–932.

MeSH terms

LinkOut - more resources