Endocrine Abstracts (2011) 26 S25.3

Xlas, in vitro functions and possible physiological and pathogenic roles

A Linglart1,2

1Pediatric Endocrinology, Bicêtre Hospital, Paris, France; 2INSERM U986, Paris, France.

The GNAS locus is a complex imprinted locus which encodes Gsa and four additional alternative transcripts including Xlas. Gsa is the ubiquitous α-subunit of the G-protein involved in major biological pathways including hormonal signaling and cell differentiation. Xlas is the only transcript sharing with Gsa the protein domain encoded by GNAS exons 2 to 13 of, which plays a key role in coupling activated receptors to adenylate cyclase stimulation. However, Xlas differs from Gsa by its tissue-specific paternal exclusive expression. Epi-genomic defects at the GNAS locus cause a series of diseases called pseudohypoparathyroidisms (PHPs) whereas post-zygotic mutations in the domain of the Gsa protein coding for the GTPase intrinsic activity cause endocrine activation and McCune–Albright syndrome (MAS). In both contexts, the symptoms were until recently attributed solely to the modified function or expression of Gsa. Recent findings clearly indicate that changes in Xlas expression or function may contribute to these phenotypes. In vitro in transfected cells that endogenously lack both Gsa and Xlas (Gnas−/− cells), human Xlas shares with Gsa the ability to couple Gsa-coupled receptors to adenylate cyclase upon agonist stimulation (including PTHR1 activation by PTH), thereby generating an increase in intracellular cAMP. Loss of function mutations of GNAS (exons 2–13) impair receptor-mediated cAMP signaling for both Gsa and Xlas; interestingly in these studies, XLas appears more potent than Gsa in mediating basal and stimulated cAMP generation. Animal models demonstrated the importance of Xlas in many processes including post-natal adaptation to feeding, energy metabolism and adipocyte biology. In humans, indirect observations suggest that XLas contributes to pre and post-natal growth and hormonal signaling in early life and that Xlas alteration in PHPs or MAS influences the patient phenotypes.

Although there is no reported human ‘model’ of XLas inactivation, the above data point to a specific role for XLas in major biological functions. However, it is still debated if Xlas potentializes, replaces and/or antagonizes Gsa function.

Article tools

My recent searches

No recent searches.