Download PDF
Horm Metab Res 2012; 44(10): 732-740
DOI: 10.1055/s-0032-1316331
Review
© Georg Thieme Verlag KG Stuttgart · New York

Relative Functions of Gαs and its Extra-large Variant XLαs in the Endocrine System

M. Bastepe
1   Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
› Author Affiliations
Further Information

Publication History

received 04 January 2012

accepted 23 May 2012

Publication Date:
22 June 2012 (online)

Also available at
    Permissions and Reprints

Abstract

Gαs is a ubiquitous signaling protein necessary for the actions of many neurotransmitters, hormones, and autocrine/paracrine factors. Loss-of-function mutations within the gene encoding Gαs, GNAS, are responsible for multiple human diseases, including Albright’s Hereditary Osteodystrophy, progressive osseous heteroplasia, and pseudohypoparathyroidism. Gain-of-function mutations in the same gene are found in various endocrine and nonendocrine tumors and in patients with McCune-Albright Syndrome and fibrous dysplasia of bone. In addition to Gαs, GNAS gives rise to multiple additional coding and noncoding transcripts. Among those, XLαs is a paternally expressed product that is partially identical to Gαs. This article reviews the cellular actions of Gαs and XLαs, focusing on the significance of XLαs relative to Gαs in mammalian physiology and human disease.

Key words

bone - parathyroid hormone - hypothyroidism - hypocalcemia - hypogonadism
 

  • References

  • 1 Weinstein LS, Gejman PV, Friedman E, Kadowaki T, Collins RM, Gershon ES, Spiegel AM. Mutations of the Gs alpha-subunit gene in Albright hereditary osteodystrophy detected by denaturing gradient gel electrophoresis. Proc Natl Acad Sci USA 1990; 87: 8287-8290
    CrossrefPubMedGoogle Scholar
  • 2 Patten JL, Johns DR, Valle D, Eil C, Gruppuso PA, Steele G, Smallwood PM, Levine MA. Mutation in the gene encoding the stimulatory G protein of adenylate cyclase in Albright's hereditary osteodystrophy. New Engl J Med 1990; 322: 1412-1419
    CrossrefPubMedGoogle Scholar
  • 3 Cabrera-Vera TM, Vanhauwe J, Thomas TO, Medkova M, Preininger A, Mazzoni MR, Hamm HE. Insights into G protein structure, function, and regulation. Endocr Rev 2003; 24: 765-781
    CrossrefPubMedGoogle Scholar
  • 4 Spiegel AM. Introduction to G-protein-coupled signal transduction and human disease. In: Spiegel AM. (ed.) G proteins, receptors, and disease. Totowa, New Jersey: Humana Press; 1998: 1-21
    CrossrefGoogle Scholar
  • 5 Kozasa T, Itoh H, Tsukamoto T, Kaziro Y. Isolation and characterization of the human Gsa gene. Proc Natl Acad Sci USA 1988; 85: 2081-2085
    CrossrefPubMedGoogle Scholar
  • 6 Gejman PV, Weinstein LS, Martinez M, Spiegel AM, Cao Q, Hsieh WT, Hoehe MR, Gershon ES. Genetic mapping of the Gs-a subunit gene (GNAS1) to the distal long arm of chromosome 20 using a polymorphism detected by denaturing gradient gel electrophoresis. Genomics 1991; 9: 782-783
    CrossrefPubMedGoogle Scholar
  • 7 Rao VV, Schnittger S, Hansmann I. G protein Gs alpha (GNAS 1), the probable candidate gene for Albright hereditary osteodystrophy, is assigned to human chromosome 20q12–q13.2. Genomics 1991; 10: 257-261
    CrossrefPubMedGoogle Scholar
  • 8 Levine MA, Modi WS, O’Brien SJ. Mapping of the gene encoding the alpha subunit of the stimulatory G protein of adenylyl cyclase (GNAS1) to 20q13.2–q13.3 in human by in situ hybridization. Genomics 1991; 11: 478-479
    CrossrefPubMedGoogle Scholar
  • 9 Yu S, Yu D, Lee E, Eckhaus M, Lee R, Corria Z, Accili D, Westphal H, Weinstein LS. Variable and tissue-specific hormone resistance in heterotrimeric Gs protein a-subunit (Gsa) knockout mice is due to tissue-specific imprinting of the Gsa gene. Proc Natl Acad Sci USA 1998; 95: 8715-8720
    Google Scholar
  • 10 Albright F, Burnett CH, Smith PH, Parson W. Pseudohypoparathyroidism – an example of “Seabright-Bantam syndrome”. Endocrinology 1942; 30: 922-932
    PubMedGoogle Scholar
  • 11 Long DN, McGuire S, Levine MA, Weinstein LS, Germain-Lee EL. Body mass index differences in pseudohypoparathyroidism type 1a versus pseudopseudohypoparathyroidism may implicate paternal imprinting of Galpha(s) in the development of human obesity. J Clin Endocrinol Metab 2007; 92: 1073-1079
    CrossrefPubMedGoogle Scholar
  • 12 Mouallem M, Shaharabany M, Weintrob N, Shalitin S, Nagelberg N, Shapira H, Zadik Z, Farfel Z. Cognitive impairment is prevalent in pseudohypoparathyroidism type Ia, but not in pseudopseudohypoparathyroidism: possible cerebral imprinting of Gsalpha. Clin Endocrinol (Oxf) 2008; 68: 233-239
    PubMedGoogle Scholar
  • 13 Levine MA, Downs Jr RW, Moses AM, Breslau NA, Marx SJ, Lasker RD, Rizzoli RE, Aurbach GD, Spiegel AM. Resistance to multiple hormones in patients with pseudohypoparathyroidism. Association with deficient activity of guanine nucleotide regulatory protein. Am J Med 1983; 74: 545-556
    Google Scholar
  • 14 Mallet E, Carayon P, Amr S, Brunelle P, Ducastelle T, Basuyau JP, de Menibus CH. Coupling defect of thyrotropin receptor and adenylate cyclase in a pseudohypoparathyroid patient. J Clin Endocrinol Metab 1982; 54: 1028-1032
    CrossrefPubMedGoogle Scholar
  • 15 Wolfsdorf JI, Rosenfield RL, Fang VS, Kobayashi R, Razdan AK, Kim MH. Partial gonadotrophin-resistance in pseudohypoparathyroidism. Acta Endocrinol (Copenh) 1978; 88: 321-328
    PubMedGoogle Scholar
  • 16 Mantovani G, Maghnie M, Weber G, De Menis E, Brunelli V, Cappa M, Loli P, Beck-Peccoz P, Spada A. Growth hormone-releasing hormone resistance in pseudohypoparathyroidism type ia: new evidence for imprinting of the Gs alpha gene. J Clin Endocrinol Metab 2003; 88: 4070-4074
    CrossrefPubMedGoogle Scholar
  • 17 Germain-Lee EL, Groman J, Crane JL, Jan de Beur SM, Levine MA. Growth hormone deficiency in pseudohypoparathyroidism type 1a: another manifestation of multihormone resistance. J Clin Endocrinol Metab 2003; 88: 4059-4069
    CrossrefPubMedGoogle Scholar
  • 18 Albright F, Forbes AP, Henneman PH. Pseudo-pseudohypoparathyroidism. Trans Assoc Am Physicians 1952; 65: 337-350
    PubMedGoogle Scholar
  • 19 Levine MA, Ahn TG, Klupt SF, Kaufman KD, Smallwood PM, Bourne HR, Sullivan KA, Van Dop C. Genetic deficiency of the alpha subunit of the guanine nucleotide-binding protein Gs as the molecular basis for Albright hereditary osteodystrophy. Proc Natl Acad Sci USA 1988; 85: 617-621
    CrossrefPubMedGoogle Scholar
  • 20 Patten JL, Levine MA. Immunochemical analysis of the a-subunit of the stimulatory G-protein of adenylyl cyclase in patients with Albright’s hereditary osteodystrophy. J Clin Endocrinol Metab 1990; 71: 1208-1214
    CrossrefPubMedGoogle Scholar
  • 21 Carter A, Bardin C, Collins R, Simons C, Bray P, Spiegel A. Reduced expression of multiple forms of the a subunit of the stimulatory GTP-binding protein in pseudohypoparathyroidism type Ia. Proc Natl Acad Sci USA 1987; 84: 7266-7269
    CrossrefPubMedGoogle Scholar
  • 22 Davies AJ, Hughes HE. Imprinting in Albright’s hereditary osteodystrophy. J Med Genet 1993; 30: 101-103
    CrossrefPubMedGoogle Scholar
  • 23 Farfel Z, Brothers VM, Brickman AS, Conte F, Neer R, Bourne HR. Pseudohypoparathyroidism: inheritance of deficient receptor-cyclase coupling activity. Proc Natl Acad Sci USA 1981; 78: 3098-3102
    Google Scholar
  • 24 Linglart A, Carel JC, Garabedian M, Le T, Mallet E, Kottler ML. GNAS1 Lesions in Pseudohypoparathyroidism Ia and Ic: Genotype Phenotype Relationship and Evidence of the Maternal Transmission of the Hormonal Resistance. J Clin Endocrinol Metab 2002; 87: 189-197
    CrossrefPubMedGoogle Scholar
  • 25 Linglart A, Mahon MJ, Kerachian MA, Berlach DM, Hendy GN, Jüppner H, 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 XLas. Endocrinology 2006; 147: 2253-2262
    CrossrefPubMedGoogle Scholar
  • 26 Thiele S, de Sanctis L, Werner R, Grotzinger J, Aydin C, Jüppner H, Bastepe M, Hiort O. Functional characterization of GNAS mutations found in patients with pseudohypoparathyroidism type Ic defines a new subgroup of pseudohypoparathyroidism affecting selectively Gsalpha-receptor interaction. Hum Mutat 2011; 32: 653-660
    CrossrefPubMedGoogle Scholar
  • 27 Liu J, Litman D, Rosenberg M, Yu S, Biesecker L, Weinstein L. A GNAS1 imprinting defect in pseudohypoparathyroidism type IB. J Clin Invest 2000; 106: 1167-1174
    Google Scholar
  • 28 Levine MA. Pseudohypoparathyroidism. In: Bilezikian JP, Raisz LG, Rodan GA. (eds.). Principles of Bone Biology. New York: Academic Press; 2002. 2. 1137-1163
    CrossrefGoogle Scholar
  • 29 Bastepe M, Pincus JE, Sugimoto T, Tojo K, Kanatani M, Azuma Y, Kruse K, Rosenbloom AL, Koshiyama H, Jüppner H. Positional dissociation between the genetic mutation responsible for pseudohypoparathyroidism type Ib and the associated methylation defect at exon A/B: evidence for a long-range regulatory element within the imprinted GNAS1 locus. Hum Mol Genet 2001; 10: 1231-1241
    CrossrefPubMedGoogle Scholar
  • 30 Liu J, Erlichman B, Weinstein LS. The stimulatory G protein a-subunit Gsa is imprinted in human thyroid glands: implications for thyroid function in pseudohypoparathyroidism types 1A and 1B. J Clin Endocrinol Metabol 2003; 88: 4336-4341
    CrossrefPubMedGoogle Scholar
  • 31 Bastepe M, Lane AH, Jüppner H. Paternal uniparental isodisomy of chromosome 20q (patUPD20q) – and the resulting changes in GNAS1 methylation – as a plausible cause of pseudohypoparathyroidism. Am J Hum Genet 2001; 68: 1283-1289
    CrossrefPubMedGoogle Scholar
  • 32 Jüppner H, Schipani E, Bastepe M, Cole DEC, Lawson ML, Mannstadt M, Hendy GN, Plotkin H, Koshiyama H, Koh T, Crawford JD, Olsen BR, Vikkula M. The gene responsible for pseudohypoparathyroidism type Ib is paternally imprinted and maps in four unrelated kindreds to chromosome 20q13.3. Proc Natl Acad Sci USA 1998; 95: 11798-11803
    CrossrefPubMedGoogle Scholar
  • 33 de Nanclares GP, Fernandez-Rebollo E, Santin I, Garcia-Cuartero B, Gaztambide S, Menendez E, Morales MJ, Pombo M, Bilbao JR, Barros F, Zazo N, Ahrens W, Jüppner H, Hiort O, Castano L, Bastepe M. Epigenetic defects of GNAS in patients with pseudohypoparathyroidism and mild features of Albright’s hereditary osteodystrophy. J Clin Endocrinol Metab 2007; 92: 2370-2373
    Google Scholar
  • 34 Unluturk U, Harmanci A, Babaoglu M, Yasar U, Varli K, Bastepe M, Bayraktar M. Molecular diagnosis and clinical characterization of pseudohypoparathyroidism type-Ib in a patient with mild Albright’s hereditary osteodystrophy-like features, epileptic seizures, and defective renal handling of uric acid. Am J Med Sci 2008; 336: 84-90
    CrossrefPubMedGoogle Scholar
  • 35 Mariot V, Maupetit-Mehouas S, Sinding C, Kottler ML, Linglart A. A maternal epimutation of GNAS leads to Albright osteodystrophy and parathyroid hormone resistance. J Clin Endocrinol Metab 2008; 93: 661-665
    Google Scholar
  • 36 Mantovani G, de Sanctis L, Barbieri AM, Elli FM, Bollati V, Vaira V, Labarile P, Bondioni S, Peverelli E, Lania AG, Beck-Peccoz P, Spada A. Pseudohypoparathyroidism and GNAS epigenetic defects: clinical evaluation of albright hereditary osteodystrophy and molecular analysis in 40 patients. J Clin Endocrinol Metab 2010; 95: 651-658
    Google Scholar
  • 37 Sanchez J, Perera E, Jan de Beur S, Ding C, Dang A, Berkovitz GD, Levine MA. Madelung-like deformity in pseudohypoparathyroidism type 1b. J Clin Endocrinol Metab 2011; 96: E1507-E1511
    CrossrefPubMedGoogle Scholar
  • 38 Bastepe M, Fröhlich LF, Hendy GN, Indridason OS, Josse RG, Koshiyama H, Körkkö J, Nakamoto JM, Rosenbloom AL, Slyper AH, Sugimoto T, Tsatsoulis A, Crawford JD, Jüppner H. Autosomal dominant pseudohypoparathyroidism type Ib is associated with a heterozygous microdeletion that likely disrupts a putative imprinting control element of GNAS. J Clin Invest 2003; 112: 1255-1263
    CrossrefPubMedGoogle Scholar
  • 39 Linglart A, Gensure RC, Olney RC, Jüppner H, Bastepe M. A Novel STX16 Deletion in Autosomal Dominant Pseudohypoparathyroidism Type Ib Redefines the Boundaries of a cis-Acting Imprinting Control Element of GNAS. Am J Hum Genet 2005; 76: 804-814
    CrossrefPubMedGoogle Scholar
  • 40 Bastepe M, Fröhlich LF, Linglart A, Abu-zahra HS, Tojo K, Ward LM, Jüppner H. Deletion of the NESP55 differentially methylated region causes loss of maternal GNAS imprints and pseudohypoparathyroidism type-Ib. Nat Genet 2005; 37: 25-37
    CrossrefPubMedGoogle Scholar
  • 41 Chillambhi S, Turan S, Hwang DY, Chen HC, Jüppner H, Bastepe M. Deletion of the Noncoding GNAS Antisense Transcript Causes Pseudohypoparathyroidism Type Ib and Biparental Defects of GNAS Methylation in cis. J Clin Endocrinol Metab 2010; 95: 3993-4002
    CrossrefPubMedGoogle Scholar
  • 42 Landis CA, Masters SB, Spada A, Pace AM, Bourne HR, Vallar L. GTPase inhibiting mutations activate the alpha chain of Gs and stimulate adenylyl cyclase in human pituitary tumours. Nature 1989; 340: 692-696
    Google Scholar
  • 43 Kalfa N, Lumbroso S, Boulle N, Guiter J, Soustelle L, Costa P, Chapuis H, Baldet P, Sultan C. Activating mutations of Gsalpha in kidney cancer. J Urol 2006; 176: 891-895
    CrossrefPubMedGoogle Scholar
  • 44 Nault JC, Fabre M, Couchy G, Pilati C, Jeannot E, Tran Van Nhieu J, Saint-Paul MC, De Muret A, Redon MJ, Buffet C, Salenave S, Balabaud C, Prevot S, Labrune P, Bioulac-Sage P, Scoazec JY, Chanson P, Zucman-Rossi J. GNAS-activating mutations define a rare subgroup of inflammatory liver tumors characterized by STAT3 activation. J Hepatol 2012; 56: 184-191
    CrossrefPubMedGoogle Scholar
  • 45 Bejar R, Stevenson K, Abdel-Wahab O, Galili N, Nilsson B, Garcia-Manero G, Kantarjian H, Raza A, Levine RL, Neuberg D, Ebert BL. Clinical effect of point mutations in myelodysplastic syndromes. N Engl J Med 2011; 364: 2496-2506
    CrossrefPubMedGoogle Scholar
  • 46 McCune D. Osteitis fibrosa cystica; the case of a nine-year old girl who also exhibits precocious puberty, multiple pigmentation of the skin and hyperthyroidism. Am J Dis Child 1936; 52: 743-744
    PubMedGoogle Scholar
  • 47 Albright F, Butler A, Hampton A, Smith P. Syndrome characterized by osteitis fibrosa disseminata, areas of pigmentation and endocrine dysfunction, with precocious puberty in females. New Engl J Med 1937; 216: 727-746
    CrossrefPubMedGoogle Scholar
  • 48 Weinstein LS, Shenker A, Gejman PV, Merino MJ, Friedman E, Spiegel AM. Activating mutations of the stimulatory G protein in the McCune-Albright syndrome. New Engl J Med 1991; 325: 1688-1695
    CrossrefPubMedGoogle Scholar
  • 49 Schwindinger WF, Francomano CA, Levine MA. Identification of a mutation in the gene encoding the alpha subunit of the stimulatory G protein of adenylyl cyclase in McCune-Albright syndrome. Proc Natl Acad Sci USA 1992; 89: 5152-5156
    CrossrefPubMedGoogle Scholar
  • 50 Happle R. The McCune-Albright syndrome: a lethal gene surviving by mosaicism. Clin Genet 1986; 29: 321-324
    PubMedGoogle Scholar
  • 51 Idowu BD, Al-Adnani M, O’Donnell P, Yu L, Odell E, Diss T, Gale RE, Flanagan AM. A sensitive mutation-specific screening technique for GNAS1 mutations in cases of fibrous dysplasia: the first report of a codon 227 mutation in bone. Histopathology 2007; 50: 691-704
    CrossrefPubMedGoogle Scholar
  • 52 Ischia R, Lovisetti-Scamihorn P, Hogue-Angeletti R, Wolkersdorfer M, Winkler H, Fischer-Colbrie R. Molecular cloning and characterization of NESP55, a novel chromogranin-like precursor of a peptide with 5-HT1B receptor antagonist activity. J Biol Chem 1997; 272: 11657-11662
    Google Scholar
  • 53 Kehlenbach RH, Matthey J, Huttner WB. XLas is a new type of G protein (Erratum in Nature 1995; 375: 253). Nature 1994; 372: 804-809
    Google Scholar
  • 54 Swaroop A, Agarwal N, Gruen JR, Bick D, Weissman SM. Differential expression of novel Gs alpha signal transduction protein cDNA species. Nucleic Acids Res 1991; 19: 4725-4729
    CrossrefPubMedGoogle Scholar
  • 55 Ishikawa Y, Bianchi C, Nadal-Ginard B, Homcy CJ. Alternative promoter and 5′ exon generate a novel Gsa mRNA. J Biol Chem 1990; 265: 8458-8462
    PubMedGoogle Scholar
  • 56 Hayward B, Bonthron D. An imprinted antisense transcript at the human GNAS1 locus. Hum Mol Genet 2000; 9: 835-841
    CrossrefPubMedGoogle Scholar
  • 57 Wroe SF, Kelsey G, Skinner JA, Bodle D, Ball ST, Beechey CV, Peters J, Williamson CM. An imprinted transcript, antisense to Nesp, adds complexity to the cluster of imprinted genes at the mouse Gnas locus. Proc Natl Acad Sci USA 2000; 97: 3342-3346
    CrossrefPubMedGoogle Scholar
  • 58 Hayward BE, Moran V, Strain L, Bonthron DT. Bidirectional imprinting of a single gene: GNAS1 encodes maternally, paternally, and biallelically derived proteins. Proc Natl Acad Sci USA 1998; 95: 15475-15480
    CrossrefPubMedGoogle Scholar
  • 59 Peters J, Wroe SF, Wells CA, Miller HJ, Bodle D, Beechey CV, Williamson CM, Kelsey G. A cluster of oppositely imprinted transcripts at the Gnas locus in the distal imprinting region of mouse chromosome 2. Proc Natl Acad Sci USA 1999; 96: 3830-3835
    CrossrefPubMedGoogle Scholar
  • 60 Hayward B, Kamiya M, Strain L, Moran V, Campbell R, Hayashizaki Y, Bronthon DT. The human GNAS1 gene is imprinted and encodes distinct paternally and biallelically expressed G proteins. Proc Natl Acad Sci USA 1998; 95: 10038-10043
    CrossrefPubMedGoogle Scholar
  • 61 Liu J, Yu S, Litman D, Chen W, Weinstein L. Identification of a methylation imprint mark within the mouse gnas locus. Mol Cell Biol 2000; 20: 5808-5817
    Google Scholar
  • 62 Zheng H, Radeva G, McCann JA, Hendy GN, Goodyer CG. Gas transcripts are biallelically expressed in the human kidney cortex: implications for pseudohypoparathyroidism type Ib. J Clin Endocrinol Metab 2001; 86: 4627-4629
    CrossrefPubMedGoogle Scholar
  • 63 Campbell R, Gosden CM, Bonthron DT. Parental origin of transcription from the human GNAS1 gene. J Med Genet 1994; 31: 607-614
    CrossrefPubMedGoogle Scholar
  • 64 Hayward B, Barlier A, Korbonits M, Grossman A, Jacquet P, Enjalbert A, Bonthron D. Imprinting of the G(s)alpha gene GNAS1 in the pathogenesis of acromegaly. J. Clin. Invest 2001; 107: R31-R36
    Google Scholar
  • 65 Mantovani G, Ballare E, Giammona E, Beck-Peccoz P, Spada A. The Gsalpha Gene: Predominant Maternal Origin of Transcription in Human Thyroid Gland and Gonads. J Clin Endocrinol Metab 2002; 87: 4736-4740
    Google Scholar
  • 66 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: 2473-2485
    CrossrefPubMedGoogle Scholar
  • 67 Li T, Vu TH, Zeng ZL, Nguyen BT, Hayward BE, Bonthron DT, Hu JF, Hoffman AR. Tissue-specific expression of antisense and sense transcripts at the imprinted Gnas locus. Genomics 2000; 69: 295-304
    CrossrefPubMedGoogle Scholar
  • 68 Pasolli H, Klemke M, Kehlenbach R, Wang Y, Huttner W. Characterization of the extra-large G protein alpha-subunit XLalphas. I. Tissue distribution and subcellular localization. J Biol Chem 2000; 275: 33622-33632
    Google Scholar
  • 69 Pasolli H, Huttner W. Expression of the extra-large G protein alpha-subunit XLalphas in neuroepithelial cells and young neurons during development of the rat nervous system. Neurosci Lett 2001; 301: 119-122
    CrossrefPubMedGoogle Scholar
  • 70 Liu Z, Segawa H, Aydin C, Reyes M, Erben RG, Weinstein LS, Chen M, Marshansky V, Frohlich LF, Bastepe M. Transgenic Overexpression of the Extra-Large Gs{alpha} Variant XL{alpha}s Enhances Gs{alpha}-Mediated Responses in the Mouse Renal Proximal Tubule in Vivo. Endocrinology 2011; 152: 1222-1233
    CrossrefPubMedGoogle Scholar
  • 71 Pignolo RJ, Xu M, Russell E, Richardson A, Kaplan J, Billings PC, Kaplan FS, Shore EM. Heterozygous inactivation of Gnas in adipose-derived mesenchymal progenitor cells enhances osteoblast differentiation and promotes heterotopic ossification. J Bone Miner Res 2011; 26: 2647-2655
    Google Scholar
  • 72 Krechowec SO, Burton KL, Newlaczyl AU, Nunn N, Vlatkovic N, Plagge A. Postnatal Changes in the Expression Pattern of the Imprinted Signalling Protein XLalphas Underlie the Changing Phenotype of Deficient Mice. PLoS One 2012; 7: e29753
    CrossrefPubMedGoogle Scholar
  • 73 Plagge A, Gordon E, Dean W, Boiani R, Cinti S, Peters J, Kelsey G. The imprinted signaling protein XLalphas is required for postnatal adaptation to feeding. Nat Genet 2004; 36: 818-826
    CrossrefPubMedGoogle Scholar
  • 74 Michienzi S, Cherman N, Holmbeck K, Funari A, Collins MT, Bianco P, Robey PG, Riminucci M. GNAS transcripts in skeletal progenitors: evidence for random asymmetric allelic expression of Gs{alpha}. Hum Mol Genet 2007; 16: 1921-1930
    CrossrefPubMedGoogle Scholar
  • 75 Mariot V, Wu JY, Aydin C, Mantovani G, Mahon MJ, Linglart A, Bastepe M. Potent constitutive cyclic AMP-generating activity of XLalphas implicates this imprinted GNAS product in the pathogenesis of McCune-Albright Syndrome and fibrous dysplasia of bone. Bone 2011; 48: 312-320
    CrossrefPubMedGoogle Scholar
  • 76 Xie T, Plagge A, Gavrilova O, Pack S, Jou W, Lai EW, Frontera M, Kelsey G, Weinstein LS. The alternative stimulatory G protein alpha-subunit XLalphas is a critical regulator of energy and glucose metabolism and sympathetic nerve activity in adult mice. J Biol Chem 2006; 281: 18989-18999
    CrossrefPubMedGoogle Scholar
  • 77 Klemke M, Pasolli H, Kehlenbach R, Offermanns S, Schultz G, Huttner W. Characterization of the extra-large G protein alpha-subunit XLalphas. II. Signal transduction properties. J Biol Chem 2000; 275: 33633-33640
    Google Scholar
  • 78 Liu Z, Turan S, Wehbi VL, Vilardaga JP, Bastepe M. Extra-long Galphas variant XLalphas protein escapes activation-induced subcellular redistribution and is able to provide sustained signaling. J Biol Chem 2011; 286: 38558-38569
    CrossrefPubMedGoogle Scholar
  • 79 Bastepe M, Gunes Y, Perez-Villamil B, Hunzelman J, Weinstein LS, Jüppner H. Receptor-Mediated Adenylyl Cyclase Activation Through XLalphas, the Extra-Large Variant of the Stimulatory G Protein alpha-Subunit. Mol Endocrinol 2002; 16: 1912-1919
    Google Scholar
  • 80 Ugur O, Jones TL. A proline-rich region and nearby cysteine residues target XLalphas to the Golgi complex region. Mol Biol Cell 2000; 11: 1421-1432
    PubMedGoogle Scholar
  • 81 Levis MJ, Bourne HR. Activation of the alpha subunit of Gs in intact cells alters its abundance, rate of degradation, and membrane avidity. J Cell Biol 1992; 119: 1297-1307
    CrossrefPubMedGoogle Scholar
  • 82 Wedegaertner PB, Bourne HR, von Zastrow M. Activation-induced subcellular redistribution of Gs alpha. Mol Biol Cell 1996; 7: 1225-1233
    PubMedGoogle Scholar
  • 83 Aydin C, Aytan N, Mahon MJ, Tawfeek HA, Kowall NW, Dedeoglu A, Bastepe M. Extralarge XLas (XXLas), a variant of stimulatory G protein alpha-subunit (Gsα), is a distinct, membrane-anchored GNAS product that can mimic Gsa. Endocrinology 2009; 150: 3567-3575
    CrossrefPubMedGoogle Scholar
  • 84 Wedegaertner PB, Chu DH, Wilson PT, Levis MJ, Bourne HR. Palmitoylation is required for signaling functions and membrane attachment of Gq alpha and Gs alpha. J Biol Chem 1993; 268: 25001-25008
    PubMedGoogle Scholar
  • 85 Wedegaertner PB, Bourne HR. Activation and depalmitoylation of Gs alpha. Cell 1994; 77: 1063-1070
    CrossrefPubMedGoogle Scholar
  • 86 Wedegaertner PB, Wilson PT, Bourne HR. Lipid modifications of trimeric G proteins. J Biol Chem 1995; 270: 503-506
    CrossrefPubMedGoogle Scholar
  • 87 Iiri T, Backlund Jr PS, Jones TL, Wedegaertner PB, Bourne HR. Reciprocal regulation of Gs alpha by palmitate and the beta gamma subunit. Proc Natl Acad Sci USA 1996; 93: 14592-14597
    CrossrefPubMedGoogle Scholar
  • 88 Evanko DS, Thiyagarajan MM, Wedegaertner PB. Interaction with Gbetagamma is required for membrane targeting and palmitoylation of Galpha(s) and Galpha(q). J Biol Chem 2000; 275: 1327-1336
    CrossrefPubMedGoogle Scholar
  • 89 Hughes TE, Zhang H, Logothetis DE, Berlot CH. Visualization of a functional Galpha q-green fluorescent protein fusion in living cells. Association with the plasma membrane is disrupted by mutational activation and by elimination of palmitoylation sites, but not be activation mediated by receptors or AlF4. J Biol Chem 2001; 276: 4227-4235
    CrossrefPubMedGoogle Scholar
  • 90 Evanko DS, Thiyagarajan MM, Siderovski DP, Wedegaertner PB. Gbeta gamma isoforms selectively rescue plasma membrane localization and palmitoylation of mutant Galphas and Galphaq. J Biol Chem 2001; 276: 23945-23953
    CrossrefPubMedGoogle Scholar
  • 91 Makita N, Sato J, Rondard P, Fukamachi H, Yuasa Y, Aldred MA, Hashimoto M, Fujita T, Iiri T. Human G(salpha) mutant causes pseudohypoparathyroidism type Ia/neonatal diarrhea, a potential cell-specific role of the palmitoylation cycle. Proc Natl Acad Sci USA 2007; 104: 17424-17429
    CrossrefPubMedGoogle Scholar
  • 92 Kaya AI, Ugur O, Oner SS, Bastepe M, Onaran HO. Coupling of {beta}2-adrenoceptors to XL{alpha}s and G{alpha}s: A new insight into ligand-induced G protein activation. J Pharmacol Exp Ther 2009; 329: 350-359
    CrossrefPubMedGoogle Scholar
  • 93 Bray P, Carter A, Simons C, Guo V, Puckett C, Kamholz J, Spiegel A, Nirenberg M. Human cDNA clones for four species of G alpha s signal transduction protein. Proc Natl Acad Sci USA 1986; 83: 8893-8897
    CrossrefPubMedGoogle Scholar
  • 94 Robishaw JD, Smigel MD, Gilman AG. Molecular basis for two forms of the G protein that stimulates adenylate cyclase. J Biol Chem 1986; 261: 9587-9590
    PubMedGoogle Scholar
  • 95 Crawford JA, Mutchler KJ, Sullivan BE, Lanigan TM, Clark MS, Russo AF. Neural expression of a novel alternatively spliced and polyadenylated Gs alpha transcript. J Biol Chem 1993; 268: 9879-9885
    PubMedGoogle Scholar
  • 96 Abramowitz J, Grenet D, Birnbaumer M, Torres HN, Birnbaumer L. XLalphas the extra-long form of the alpha-subunit of the Gs G protein, is significantly longer than suspected, and so is its companion Alex. Proc Natl Acad Sci USA 2004; 101: 8366-8371
    CrossrefPubMedGoogle Scholar
  • 97 Klemke M, Kehlenbach RH, Huttner WB. Two overlapping reading frames in a single exon encode interacting proteins – a novel way of gene usage. Embo J 2001; 20: 3849-3860
    CrossrefPubMedGoogle Scholar
  • 98 Freson K, Jaeken J, Van Helvoirt M, de Zegher F, Wittevrongel C, Thys C, Hoylaerts MF, Vermylen J, Van Geet C. Functional polymorphisms in the paternally expressed XLalphas and its cofactor ALEX decrease their mutual interaction and enhance receptor-mediated cAMP formation. Hum Mol Genet 2003; 12: 1121-1130
    CrossrefPubMedGoogle Scholar
  • 99 Yu S, Castle A, Chen M, Lee R, Takeda K, Weinstein LS. Increased insulin sensitivity in Gsalpha knockout mice. J Biol Chem 2001; 276: 19994-19998
    CrossrefPubMedGoogle Scholar
  • 100 Yu S, Gavrilova O, Chen H, Lee R, Liu J, Pacak K, Parlow A, Quon M, Reitman M, Weinstein L. Paternal versus maternal transmission of a stimulatory G-protein alpha subunit knockout produces opposite effects on energy metabolism. J Clin Invest 2000; 105: 615-623
    CrossrefPubMedGoogle Scholar
  • 101 Chen M, Haluzik M, Wolf NJ, Lorenzo J, Dietz KR, Reitman ML, Weinstein LS. Increased insulin sensitivity in paternal Gnas knockout mice is associated with increased lipid clearance. Endocrinology 2004; 145: 4094-4102
    CrossrefPubMedGoogle Scholar
  • 102 Skinner J, Cattanach B, Peters J. The imprinted oedematous-small mutation on mouse chromosome 2 identifies new roles for gnas and gnasxl in development. Genomics 2002; 80: 373
    CrossrefPubMedGoogle Scholar
  • 103 Williamson CM, Ball ST, Nottingham WT, Skinner JA, Plagge A, Turner MD, Powles N, Hough T, Papworth D, Fraser WD, Maconochie M, Peters J. A cis-acting control region is required exclusively for the tissue-specific imprinting of Gnas. Nat Genet 2004; 36: 894-899
    CrossrefPubMedGoogle Scholar
  • 104 Kelly ML, Moir L, Jones L, Whitehill E, Anstee QM, Goldin RD, Hough A, Cheeseman M, Jansson JO, Peters J, Cox RD. A missense mutation in the non-neural G-protein alpha-subunit isoforms modulates susceptibility to obesity. Int J Obes (Lond) 2009; 33: 507-518
    CrossrefPubMedGoogle Scholar
  • 105 Eaton SA, Williamson CM, Ball ST, Beechey CV, Moir L, Edwards J, Teboul L, Maconochie M, Peters J. New Mutations at the Imprinted Gnas Cluster Show Gene Dosage Effects of Gsalpha in Postnatal Growth and Implicate XLalphas in Bone and Fat Metabolism but Not in Suckling. Mol Cell Biol 2012; 32: 1017-1029
    CrossrefPubMedGoogle Scholar
  • 106 Chen M, Gavrilova O, Liu J, Xie T, Deng C, Nguyen AT, Nackers LM, Lorenzo J, Shen L, Weinstein LS. Alternative Gnas gene products have opposite effects on glucose and lipid metabolism. Proc Natl Acad Sci USA 2005; 102: 7386-7391
    CrossrefPubMedGoogle Scholar
  • 107 Germain-Lee EL, Schwindinger W, Crane JL, Zewdu R, Zweifel LS, Wand G, Huso DL, Saji M, Ringel MD, Levine MA. A Mouse Model of Albright Hereditary Osteodystrophy Generated by Targeted Disruption of Exon 1 of the Gnas Gene. Endocrinology 2005; 146: 4697-4709
    CrossrefPubMedGoogle Scholar
  • 108 Genevieve D, Sanlaville D, Faivre L, Kottler ML, Jambou M, Gosset P, Boustani-Samara D, Pinto G, Ozilou C, Abeguile G, Munnich A, Romana S, Raoul O, Cormier-Daire V, Vekemans M. Paternal deletion of the GNAS imprinted locus (including Gnasxl) in two girls presenting with severe pre- and post-natal growth retardation and intractable feeding difficulties. Eur J Hum Genet 2005; 13: 1033-1039
    CrossrefPubMedGoogle Scholar
  • 109 Aldred MA, Aftimos S, Hall C, Waters KS, Thakker RV, Trembath RC, Brueton L. Constitutional deletion of chromosome 20q in two patients affected with albright hereditary osteodystrophy. Am J Med Genet 2002; 113: 167-172
    CrossrefPubMedGoogle Scholar
  • 110 Chudoba I, Franke Y, Senger G, Sauerbrei G, Demuth S, Beensen V, Neumann A, Hansmann I, Claussen U. Maternal UPD 20 in a hyperactive child with severe growth retardation. Eur J Hum Genet 1999; 7: 533-540
    CrossrefPubMedGoogle Scholar
  • 111 Lebrun M, Richard N, Abeguile G, David A, Coeslier Dieux A, Journel H, Lacombe D, Pinto G, Odent S, Salles JP, Taieb A, Gandon-Laloum S, Kottler ML. Progressive osseous heteroplasia: a model for the imprinting effects of GNAS inactivating mutations in humans. J Clin Endocrinol Metab 2010; 95: 3028-3038
    CrossrefPubMedGoogle Scholar
  • 112 Kaplan FS, Shore EM. Progressive osseous heteroplasia. J Bone Miner Res 2000; 15: 2084-2094
    CrossrefPubMedGoogle Scholar
  • 113 Shore EM, Ahn J, Jan de Beur S, Li M, Xu M, Gardner RJ, Zasloff MA, Whyte MP, Levine MA, Kaplan FS. Paternally inherited inactivating mutations of the GNAS1 gene in progressive osseous heteroplasia. N Engl J Med 2002; 346: 99-106
    Google Scholar
  • 114 Faust RA, Shore EM, Stevens CE, Xu M, Shah S, Phillips CD, Kaplan FS. Progressive osseous heteroplasia in the face of a child. Am J Med Genet A 2003; 118: 71-75
    PubMedGoogle Scholar
  • 115 Chan I, Hamada T, Hardman C, McGrath JA, Child FJ. Progressive osseous heteroplasia resulting from a new mutation in the GNAS1 gene. Clin Exp Dermatol 2004; 29: 77-80
    CrossrefPubMedGoogle Scholar
  • 116 Adegbite NS, Xu M, Kaplan FS, Shore EM, Pignolo RJ. Diagnostic and mutational spectrum of progressive osseous heteroplasia (POH) and other forms of GNAS-based heterotopic ossification. Am J Med Genet A 2008; 146A: 1788-1796
    CrossrefPubMedGoogle Scholar
  • 117 Mantovani G, Bondioni S, Lania AG, Corbetta S, de Sanctis L, Cappa M, Di Battista E, Chanson P, Beck-Peccoz P, Spada A. Parental origin of Gsalpha mutations in the McCune-Albright syndrome and in isolated endocrine tumors. J Clin Endocrinol Metab 2004; 89: 3007-3009
    CrossrefPubMedGoogle Scholar
  • 118 Cattanach BM, Peters J, Ball S, Rasberry C. Two imprinted gene mutations: three phenotypes. Hum Mol Genet 2000; 9: 2263-2273
    CrossrefPubMedGoogle Scholar