The D153del Mutation in GNB3 Gene Causes Tissue Specific Signalling Patterns and an Abnormal Renal Morphology in Rge Chickens

Hemanth Tummala, Stewart Fleming, Paul M. Hocking, Daniel Wehner, Zahid Naseem, Manir Ali, Christopher F. Inglehearn, Nikolai Zhelev, Douglas H. Lester

    Research output: Contribution to journalArticle

    7 Citations (Scopus)

    Abstract

    Background: The GNB3 gene is expressed in cone but not rod photoreceptors of vertebrates, where it acts as the beta 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.

    Principal Findings: 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 G beta 3 protein subunit that, together with different G gamma and G alpha 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.

    Significance: 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.

    Original languageEnglish
    Article numbere21156
    Pages (from-to)-
    Number of pages11
    JournalPLoS ONE
    Volume6
    Issue number8
    DOIs
    Publication statusPublished - 22 Aug 2011

    Keywords

    • PROTEIN BETA-3 SUBUNIT
    • HETEROTRIMERIC G-PROTEINS
    • GAMMA-SUBUNITS
    • SPLICE VARIANT
    • RETINAL DEGENERATION
    • COUPLED RECEPTORS
    • GOLGI MEMBRANES
    • 825T ALLELE
    • CYCLIC-GMP
    • KINASE

    Cite this

    Tummala, Hemanth ; Fleming, Stewart ; Hocking, Paul M. ; Wehner, Daniel ; Naseem, Zahid ; Ali, Manir ; Inglehearn, Christopher F. ; Zhelev, Nikolai ; Lester, Douglas H. / The D153del Mutation in GNB3 Gene Causes Tissue Specific Signalling Patterns and an Abnormal Renal Morphology in Rge Chickens. In: PLoS ONE. 2011 ; Vol. 6, No. 8. pp. -.
    @article{59b272a0a935428984c9fb85c72c670a,
    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 beta 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.Principal Findings: 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 G beta 3 protein subunit that, together with different G gamma and G alpha 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.Significance: 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.",
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    author = "Hemanth Tummala and Stewart Fleming and Hocking, {Paul M.} and Daniel Wehner and Zahid Naseem and Manir Ali and Inglehearn, {Christopher F.} and Nikolai Zhelev and Lester, {Douglas H.}",
    year = "2011",
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    Tummala, H, Fleming, S, Hocking, PM, Wehner, D, Naseem, Z, Ali, M, Inglehearn, CF, Zhelev, N & Lester, DH 2011, 'The D153del Mutation in GNB3 Gene Causes Tissue Specific Signalling Patterns and an Abnormal Renal Morphology in Rge Chickens', PLoS ONE, vol. 6, no. 8, e21156, pp. -. https://doi.org/10.1371/journal.pone.0021156

    The D153del Mutation in GNB3 Gene Causes Tissue Specific Signalling Patterns and an Abnormal Renal Morphology in Rge Chickens. / Tummala, Hemanth; Fleming, Stewart; Hocking, Paul M.; Wehner, Daniel; Naseem, Zahid; Ali, Manir; Inglehearn, Christopher F.; Zhelev, Nikolai; Lester, Douglas H.

    In: PLoS ONE, Vol. 6, No. 8, e21156, 22.08.2011, p. -.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - The D153del Mutation in GNB3 Gene Causes Tissue Specific Signalling Patterns and an Abnormal Renal Morphology in Rge Chickens

    AU - Tummala, Hemanth

    AU - Fleming, Stewart

    AU - Hocking, Paul M.

    AU - Wehner, Daniel

    AU - Naseem, Zahid

    AU - Ali, Manir

    AU - Inglehearn, Christopher F.

    AU - Zhelev, Nikolai

    AU - Lester, Douglas H.

    PY - 2011/8/22

    Y1 - 2011/8/22

    N2 - Background: The GNB3 gene is expressed in cone but not rod photoreceptors of vertebrates, where it acts as the beta 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.Principal Findings: 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 G beta 3 protein subunit that, together with different G gamma and G alpha 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.Significance: 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.

    AB - Background: The GNB3 gene is expressed in cone but not rod photoreceptors of vertebrates, where it acts as the beta 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.Principal Findings: 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 G beta 3 protein subunit that, together with different G gamma and G alpha 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.Significance: 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.

    KW - PROTEIN BETA-3 SUBUNIT

    KW - HETEROTRIMERIC G-PROTEINS

    KW - GAMMA-SUBUNITS

    KW - SPLICE VARIANT

    KW - RETINAL DEGENERATION

    KW - COUPLED RECEPTORS

    KW - GOLGI MEMBRANES

    KW - 825T ALLELE

    KW - CYCLIC-GMP

    KW - KINASE

    U2 - 10.1371/journal.pone.0021156

    DO - 10.1371/journal.pone.0021156

    M3 - Article

    VL - 6

    SP - -

    JO - PLoS ONE

    JF - PLoS ONE

    SN - 1932-6203

    IS - 8

    M1 - e21156

    ER -