Document Detail


Patients with mutations in Gsalpha have reduced activation of a downstream target in epithelial tissues due to haploinsufficiency.
MedLine Citation:
PMID:  17652219     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
CONTEXT: Patients with Albright hereditary osteodystrophy (AHO) have defects in stimulatory G protein signaling due to loss of function mutations in GNAS. The mechanism by which these mutations lead to the AHO phenotype has been difficult to establish due to the inaccessibility of the affected tissues. OBJECTIVE: The objective of the study was to gain insight into the downstream consequences of abnormal stimulatory G protein signaling in human epithelial tissues. PATIENTS AND DESIGN: We assessed transcription of GNAS and Gsalpha-stimulated activation of the cystic fibrosis transmembrane conductance regulator (CFTR) in AHO patients, compared with normal controls and patients with cystic fibrosis. MAIN OUTCOME MEASURES: Relative expression of Gsalpha transcripts from each parental GNAS allele and cAMP measurements from nasal epithelial cells were compared among normal controls and AHO patients. In vivo measurements of CFTR function, pulmonary function, and pancreatic function were assessed in AHO patients. RESULTS: GNAS was expressed equally from each allele in normals and two of five AHO patients. cAMP generation was significantly reduced in nasal respiratory epithelial cells from AHO patients, compared with normal controls (0.4 vs. 0.6, P = 0.0008). Activation of CFTR in vivo in nasal (P = 0.0065) and sweat gland epithelia (P = 0.01) of AHO patients was significantly reduced from normal. In three patients, the reduction in activity was comparable with patients with cystic fibrosis due to mutations in CFTR. Yet no AHO patients had pulmonary or pancreatic disease consistent with cystic fibrosis. CONCLUSIONS: In humans, haploinsufficiency of GNAS causes a significant reduction in the activation of the downstream target, CFTR, in vivo.
Authors:
Stephanie C Hsu; Joshua D Groman; Christian A Merlo; Kathleen Naughton; Pamela L Zeitlin; Emily L Germain-Lee; Michael P Boyle; Garry R Cutting
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2007-07-24
Journal Detail:
Title:  The Journal of clinical endocrinology and metabolism     Volume:  92     ISSN:  0021-972X     ISO Abbreviation:  J. Clin. Endocrinol. Metab.     Publication Date:  2007 Oct 
Date Detail:
Created Date:  2007-10-15     Completed Date:  2007-11-21     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  0375362     Medline TA:  J Clin Endocrinol Metab     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3941-8     Citation Subset:  AIM; IM    
Affiliation:
Department of Pediatric Endocrinology , Johns Hopkins University, 733 North Broadway, Suite 551, Baltimore, Maryland 21205, USA. shsu8@jhmi.edu
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MeSH Terms
Descriptor/Qualifier:
Adolescent
Adult
Child
Cyclic AMP / metabolism
Cystic Fibrosis / genetics*,  metabolism
Cystic Fibrosis Transmembrane Conductance Regulator / metabolism*
Female
Fibrous Dysplasia, Polyostotic / genetics*,  metabolism
GTP-Binding Protein alpha Subunits, Gs / genetics*,  metabolism*
Humans
Male
Middle Aged
Mutation
Nasal Mucosa / metabolism
Phenotype
Polymerase Chain Reaction / methods
Signal Transduction / physiology
Grant Support
ID/Acronym/Agency:
F32 DK067748/DK/NIDDK NIH HHS; K12 HD27799/HD/NICHD NIH HHS; R01 HL68927/HL/NHLBI NIH HHS; R37 DK 44003/DK/NIDDK NIH HHS; T32 DK007751/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/CFTR protein, human; 126880-72-6/Cystic Fibrosis Transmembrane Conductance Regulator; 60-92-4/Cyclic AMP; EC 3.6.5.1/GTP-Binding Protein alpha Subunits, Gs

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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