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


METHODS
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.


METHODS
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.
Hsu
Stephanie C
SC
Department of Pediatric Endocrinology , Johns Hopkins University, 733 North Broadway, Suite 551, Baltimore, Maryland 21205, USA. shsu8@jhmi.edu
Groman
Joshua D
JD
Merlo
Christian A
CA
Naughton
Kathleen
K
Zeitlin
Pamela L
PL
Germain-Lee
Emily L
EL
Boyle
Michael P
MP
Cutting
Garry R
GR
D000293:Adolescent; D000328:Adult; D002648:Child; D000242:Cyclic AMP / Q000378:metabolism; D003550:Cystic Fibrosis / Q000235:genetics* / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism*; D005260:Female; D005359:Fibrous Dysplasia, Polyostotic / Q000235:genetics* / Q000378:metabolism; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009297:Nasal Mucosa / Q000378:metabolism; D010641:Phenotype; D016133:Polymerase Chain Reaction / Q000379:methods; D015398:Signal Transduction / Q000502:physiology
C505032:CFTR protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000242:Cyclic AMP; D019205:GTP-Binding Protein alpha Subunits, Gs