title: The D153del mutation in GNB3 gene causes tissue specific signalling patterns and an abnormal renal morphology in Rge chickens.
abstract: BACKGROUND
  The GNB3 gene is expressed in cone but not rod photoreceptors of vertebrates, where it acts as the β transducin subunit in the colour visual transduction process. A naturally occurring mutation 'D153del' in the GNB3 gene causes the recessively inherited blinding phenotype retinopathy globe enlarged (rge) disease in chickens. GNB3 is however also expressed in most other vertebrate tissues suggesting that the D153del mutation may exert pathological effects that outlie from eye.
  
  
  RESULTS
  Recombinant studies in COS-7 cells that were transfected with normal and mutant recombinant GNB3 constructs and subjected to cycloheximide chase showed that the mutant GNB3d protein had a much shorter half life compared to normal GNB3. GNB3 codes for the Gβ3 protein subunit that, together with different Gγ and Gα subunits, activates and regulates phosphorylation cascades in different tissues. As expected, the relative levels of cGMP and cAMP secondary messengers and their activated kinases such as MAPK, AKT and GRK2 were also found to be altered significantly in a tissue specific manner in rge chickens. Histochemical analysis on kidney tissue sections, from rge homozygous affected chickens, showed the chickens had enlargement of the glomerular capsule, causing glomerulomegaly and tubulointerstitial inflammation whereas other tissues (brain, heart, liver, pancreas) were unaffected.
  
  
  CONCLUSIONS
  These findings confirm that the D153del mutation in GNB3 gene targets GNB3 protein to early degradation. Lack of GNB3 signalling causes reduced phosphorylation activity of ERK2 and AKT leading to severe pathological phenotypes such as blindness and renal abnormalities in rge chickens.
authors: School of Contemporary Sciences, University of Abertay Dundee, Dundee, Scotland, United Kingdom.
authors: Hemanth
authors: H
authors: Tummala
authors: Stewart
authors: S
authors: Fleming
authors: Paul M
authors: PM
authors: Hocking
authors: Daniel
authors: D
authors: Wehner
authors: Zahid
authors: Z
authors: Naseem
authors: Manir
authors: M
authors: Ali
authors: Christopher F
authors: CF
authors: Inglehearn
authors: Nikolai
authors: N
authors: Zhelev
authors: Douglas H
authors: DH
authors: Lester
mesh_terms: D000818:Animals; D001715:Bird Diseases / Q000235:genetics*; D019556:COS Cells; D002645:Chickens / Q000235:genetics*; D002522:Chlorocebus aethiops; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000378:metabolism; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics*; D007668:Kidney / Q000002:abnormalities* / Q000378:metabolism / Q000473:pathology; D050505:Mutant Proteins / Q000378:metabolism; D009928:Organ Specificity / Q000235:genetics; D010766:Phosphorylation; D021122:Protein Subunits / Q000378:metabolism; D021381:Protein Transport; D059748:Proteolysis; D015290:Second Messenger Systems; D017384:Sequence Deletion / Q000235:genetics*; D015398:Signal Transduction
chemical_list: C454420:G-protein beta3 subunit; D050505:Mutant Proteins; D021122:Protein Subunits; D000242:Cyclic AMP; D054769:G-Protein-Coupled Receptor Kinase 2; D020962:Heterotrimeric GTP-Binding Proteins; D006152:Cyclic GMP