Advertisement
JBC

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Originally published In Press as doi:10.1074/jbc.M006032200 on October 11, 2000

J. Biol. Chem., Vol. 276, Issue 1, 165-171, January 5, 2001
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
276/1/165    most recent
M006032200v1
Right arrow Submit a Letter to Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Wu, W.-I.
Right arrow Articles by Levine, M. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Wu, W.-I.
Right arrow Articles by Levine, M. A.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

Selective Resistance to Parathyroid Hormone Caused by a Novel Uncoupling Mutation in the Carboxyl Terminus of Galpha s
A CAUSE OF PSEUDOHYPOPARATHYROIDISM TYPE Ib*

Wei-I. WuDagger , William F. SchwindingerDagger , Luis F. Aparicio§, and Michael A. LevineDagger

From the Dagger  Division of Pediatric Endocrinology and the Ilyssa Center for Molecular and Cellular Endocrinology, Department of Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287 and § Metabolic Disease Associates, Erie, Pennsylvania 16507

Gs is a heterotrimeric (alpha , beta , and gamma  chains) G protein that couples heptahelical plasma membrane receptors to stimulation of adenylyl cyclase. Inactivation of one GNAS1 gene allele encoding the alpha  chain of Gs (Galpha s) causes pseudohypoparathyroidism type Ia. Affected subjects have resistance to parathyroid hormone (PTH) and other hormones that activate adenylyl cyclase plus somatic features termed Albright hereditary osteodystrophy. By contrast, subjects with pseudohypoparathyroidism type Ib have hormone resistance that is limited to PTH and lack Albright hereditary osteodystrophy. The molecular basis for pseudohypoparathyroidism type Ib is unknown. We analyzed the GNAS1 gene for mutations using polymerase chain reaction to amplify genomic DNA from three brothers with pseudohypoparathyroidism type Ib. We identified a novel heterozygous 3-base pair deletion causing loss of isoleucine 382 in the three affected boys and their clinically unaffected mother and maternal grandfather. This mutation was absent in other family members and 15 additional unrelated subjects with pseudohypoparathyroidism type Ib. To characterize the signaling properties of the mutant Galpha s, we used site-directed mutagenesis to introduce the isoleucine 382 deletion into a wild type Galpha s cDNA, transfected HEK293 cells with either wild type or mutant Galpha s cDNA, plus cDNAs encoding heptahelical receptors for PTH, thyrotropic hormone, or luteinizing hormone, and we measured cAMP production in response to hormone stimulation. The mutant Galpha s protein was unable to interact with the receptor for PTH but showed normal coupling to the other coexpressed heptahelical receptors. These results provide evidence of selective uncoupling of the mutant Galpha s from PTH receptors and explain PTH-specific hormone resistance in these three brothers with pseudohypoparathyroidism type Ib. The absence of PTH resistance in the mother and maternal grandfather who carry the same mutation is consistent with current models of paternal imprinting of the GNAS1 gene.

* This work was supported in part by United States Public Health Service Grant DK34281 (to M. A. L.) and by General Clinical Research Center Grant RR0035 from the National Institutes of Health.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Division of Pediatric Endocrinology, Johns Hopkins University School of Medicine, Park Bldg., Rm. 211, 600 N. Wolfe St., Baltimore, Maryland 21287. Tel.: 410-955-6463; Fax: 410-955-9773; E-mail: mlevine@jhmi.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?


This article has been cited by other articles:


Home page
 Clin. Chem.Home page
A. Weinhaeusel, S. Thiele, M. Hofner, O. Hiort, and C. Noehammer
PCR-Based Analysis of Differentially Methylated Regions of GNAS Enables Convenient Diagnostic Testing of Pseudohypoparathyroidism Type Ib
Clin. Chem., September 1, 2008; 54(9): 1537 - 1545.
[Abstract] [Full Text] [PDF]

Home page
 J EndocrinolHome page
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]

Home page
 EndocrinologyHome page
A. Linglart, M. J. Mahon, M. A. Kerachian, D. M. Berlach, G. N. Hendy, H. Juppner, and M. Bastepe
Coding GNAS Mutations Leading to Hormone Resistance Impair in Vitro Agonist- and Cholera Toxin-Induced Adenosine Cyclic 3',5'-Monophosphate Formation Mediated by Human XL{alpha}s
Endocrinology, May 1, 2006; 147(5): 2253 - 2262.
[Abstract] [Full Text] [PDF]

Home page
 IBMS BoneKEyHome page
M. Bastepe and H. Juppner
Pseudohypoparathyroidism, Gs{alpha}, and the GNAS Locus
IBMS BoneKEy, December 1, 2005; 2(12): 20 - 32.
[Full Text] [PDF]

Home page
 Physiol. Rev.Home page
N. Wettschureck and S. Offermanns
Mammalian G Proteins and Their Cell Type Specific Functions
Physiol Rev, October 1, 2005; 85(4): 1159 - 1204.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
L. S. Weinstein, J. Liu, A. Sakamoto, T. Xie, and M. Chen
Minireview: GNAS: Normal and Abnormal Functions
Endocrinology, December 1, 2004; 145(12): 5459 - 5464.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
G. Mantovani, M. Maghnie, G. Weber, E. De Menis, V. Brunelli, M. Cappa, P. Loli, P. Beck-Peccoz, and A. Spada
Growth Hormone-Releasing Hormone Resistance in Pseudohypoparathyroidism Type Ia: New Evidence for Imprinting of the Gs{alpha} Gene
J. Clin. Endocrinol. Metab., September 1, 2003; 88(9): 4070 - 4074.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
J. F. Raposo, L. G. Sobrinho, and H. G. Ferreira
A Minimal Mathematical Model of Calcium Homeostasis
J. Clin. Endocrinol. Metab., September 1, 2002; 87(9): 4330 - 4340.
[Abstract] [Full Text] [PDF]

Home page
 Endocr. Rev.Home page
L. S. Weinstein, S. Yu, D. R. Warner, and J. Liu
Endocrine Manifestations of Stimulatory G Protein {alpha}-Subunit Mutations and the Role of Genomic Imprinting
Endocr. Rev., October 1, 2001; 22(5): 675 - 705.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
M. Bastepe, J. E. Pincus, T. Sugimoto, K. Tojo, M. Kanatani, Y. Azuma, K. Kruse, A. L. Rosenbloom, H. Koshiyama, and H. Juppner
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., June 1, 2001; 10(12): 1231 - 1241.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
 All ASBMB Journals   Molecular and Cellular Proteomics 
 Journal of Lipid Research   ASBMB Today 
Copyright © 2001 by the American Society for Biochemistry and Molecular Biology.
Advertisement
spacer
Advertisement
Advertisement