This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Linglart, A. Articles by Bastepe, M. Search for Related Content PubMed PubMed Citation Articles by Linglart, A. Articles by Bastepe, M.

Coding GNAS Mutations Leading to Hormone Resistance Impair in Vitro Agonist- and Cholera Toxin-Induced Adenosine Cyclic 3',5'-Monophosphate Formation Mediated by Human XLs

Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School (A.L., M.J.M., M.B.), Boston, Massachusetts 02114; Pediatric Endocrinology and Institut National de la Santé et de la Recherche Médicale, Unité 561, Saint Vincent de Paul Hospital (A.L.), Paris, France; Departments of Medicine, Physiology, and Human Genetics, McGill University (M.A.K., D.M.B., G.N.H.), and Calcium Research Laboratory, and Hormones and Cancer Research Unit, Royal Victoria Hospital (M.A.K., D.M.B., G.N.H.), Montréal, Québec, Canada; and Pediatric Nephrology Unit, MassGeneral Hospital for Children and Harvard Medical School (H.J.), Boston, Massachusetts 02114

Address all correspondence and requests for reprints to: Dr. Murat Bastepe, Endocrine Unit, Massachusetts General Hospital, 50 Blossom Street, Thier 501, Boston, Massachusetts 02114. E-mail: bastepe{at}helix.mgh.harvard.edu.

Most loss of function mutations of GNAS identified in different forms of pseudohypoparathyroidism disrupt not only the stimulatory G protein -subunit (Gs), but also its paternally expressed variant, XLs. However, the possibility that XLs deficiency contributes to disease pathogenesis has remained unexplored. We therefore examined the signaling property of human XLs and the effects of one novel (XLs^H704P or Gs^H362P) and two previously described (XLs^DelI724 and XLs^Y733X or Gs^DelI382 and Gs^Y391X, respectively) GNAS mutations on either XLs or Gs activity. Confocal immunofluorescence microscopy detected human XLs immunoreactivity at the plasma membrane of transduced mouse embryonic fibroblasts null for endogenous Gs and XLs (Gnas^E2–/E2– cells). Cholera toxin- and isoproterenol-induced cAMP accumulation in Gnas^E2–/E2– cells transiently expressing wild-type human XLs was similar to that in cells transiently expressing wild-type Gs. Human XLs, like Gs, mediated PTH-induced cAMP accumulation in Gnas^E2–/E2– cells coexpressing PTH receptor type 1 and either of these proteins. Moreover, overexpression of human XLs or Gs markedly enhanced the PTH-induced cAMP accumulation in opossum kidney cells that endogenously express PTH receptor type 1. In contrast, each XLs mutant failed to mediate isoproterenol- and PTH-induced cAMP accumulation in transduced Gnas^E2–/E2– cells. XLs^DelI724 showed a reduced cholera toxin response over the basal level compared with wild-type XLs, and XLs^H704P completely failed to respond to cholera toxin. These findings were comparable to those observed with each corresponding Gs mutant transiently expressed in Gnas^E2–/E2– cells. Thus, mutations that typically inactivate Gs also impair XLs activity, consistent with a possible role for XLs deficiency in diseases caused by paternal GNAS mutations.

This article has been cited by other articles:

				V. Mariot, S. Maupetit-Mehouas, C. Sinding, M.-L. Kottler, and A. Linglart A Maternal Epimutation of GNAS Leads to Albright Osteodystrophy and Parathyroid Hormone Resistance J. Clin. Endocrinol. Metab., March 1, 2008; 93(3): 661 - 665. [Abstract] [Full Text] [PDF]

				A. Plagge, G. Kelsey, and E. L Germain-Lee Physiological functions of the imprinted Gnas locus and its protein variants G{alpha}s and XL{alpha}s in human and mouse J. Endocrinol., February 1, 2008; 196(2): 193 - 214. [Abstract] [Full Text] [PDF]

				N. Makita, J. Sato, P. Rondard, H. Fukamachi, Y. Yuasa, M. A. Aldred, M. Hashimoto, T. Fujita, and T. Iiri Human Gs{alpha} mutant causes pseudohypoparathyroidism type Ia/neonatal diarrhea, a potential cell-specific role of the palmitoylation cycle PNAS, October 30, 2007; 104(44): 17424 - 17429. [Abstract] [Full Text] [PDF]

				S. Michienzi, N. Cherman, K. Holmbeck, A. Funari, M. T. Collins, P. Bianco, P. G. Robey, and M. Riminucci GNAS transcripts in skeletal progenitors: evidence for random asymmetric allelic expression of Gs{alpha} Hum. Mol. Genet., August 15, 2007; 16(16): 1921 - 1930. [Abstract] [Full Text] [PDF]