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Submitted on November 22, 2005
Accepted on February 3, 2006
s
Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, Pediatric Endocrinology and INSERM U561, Saint Vincent de Paul Hospital, Paris, France, Departments of Medicine, Physiology and Human Genetics, McGill University, and Calcium Research Laboratory, and Hormones and Cancer Research Unit, Royal Victoria Hospital, Montreal, Quebec, Canada, Pediatric Nephrology Unit, MassGeneral Hospital for Children and Harvard Medical School, Boston, Massachusetts
* To whom correspondence should be addressed. E-mail: bastepe{at}helix.mgh.harvard.edu.
Most loss-of-function mutations of GNAS identified in different forms of pseudohypoparathyroidism disrupt not only 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 (XLsH704P or GsH362P) and two previously described (XLsDelI724 and XLsY733X or GsDelI382 and GsY391X, 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 (GnasE2-/E2- cells). Cholera toxin- and isoproterenol-induced cAMP accumulation in GnasE2-/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 GnasE2-/E2- cells co-expressing PTH receptor type-1 (PTHR1) 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 PTHR1. In contrast, each XLs mutant failed to mediate isoproterenol- and PTH-induced cAMP accumulation in transduced GnasE2-/E2- cells. XLsDelI724 showed a reduced cholera-toxin response over the basal when compared with wild-type XLs, and XLsH704P completely failed to respond to cholera-toxin. These findings were comparable to those observed with each corresponding Gs mutant transiently expressed in GnasE2-/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.
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