Patients with mutations in Gsα have reduced activation of a downstream target in epithelial tissues due to haploinsufficiency

Stephanie C. Hsu, Joshua D. Groman, Christian A. Merlo, Kathleen Naughton, Pamela L. Zeitlin, Emily L. Germain-Lee, Michael P. Boyle, Garry R. Cutting

Research output: Contribution to journalArticle

Abstract

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 Gsα-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 Gsα 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.

Original languageEnglish (US)
Pages (from-to)3941-3948
Number of pages8
JournalJournal of Clinical Endocrinology and Metabolism
Volume92
Issue number10
DOIs
StatePublished - Oct 2007
Externally publishedYes

Fingerprint

Haploinsufficiency
Cystic Fibrosis Transmembrane Conductance Regulator
Epithelium
Chemical activation
Tissue
Mutation
GTP-Binding Proteins
Nose
Cystic Fibrosis
Transcription
Epithelial Cells
Alleles
Defects
Albright's hereditary osteodystrophy
Sweat Glands
Pancreatic Diseases
Lung Diseases

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

Cite this

Patients with mutations in Gsα have reduced activation of a downstream target in epithelial tissues due to haploinsufficiency. / Hsu, Stephanie C.; Groman, Joshua D.; Merlo, Christian A.; Naughton, Kathleen; Zeitlin, Pamela L.; Germain-Lee, Emily L.; Boyle, Michael P.; Cutting, Garry R.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 92, No. 10, 10.2007, p. 3941-3948.

Research output: Contribution to journalArticle

Hsu, Stephanie C. ; Groman, Joshua D. ; Merlo, Christian A. ; Naughton, Kathleen ; Zeitlin, Pamela L. ; Germain-Lee, Emily L. ; Boyle, Michael P. ; Cutting, Garry R. / Patients with mutations in Gsα have reduced activation of a downstream target in epithelial tissues due to haploinsufficiency. In: Journal of Clinical Endocrinology and Metabolism. 2007 ; Vol. 92, No. 10. pp. 3941-3948.
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abstract = "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 Gsα-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 Gsα 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.",
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T1 - Patients with mutations in Gsα have reduced activation of a downstream target in epithelial tissues due to haploinsufficiency

AU - Hsu, Stephanie C.

AU - Groman, Joshua D.

AU - Merlo, Christian A.

AU - Naughton, Kathleen

AU - Zeitlin, Pamela L.

AU - Germain-Lee, Emily L.

AU - Boyle, Michael P.

AU - Cutting, Garry R.

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N2 - 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 Gsα-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 Gsα 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.

AB - 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 Gsα-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 Gsα 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.

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