Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Science 17 May 1996:
Vol. 272. no. 5264, pp. 1026 - 1029
DOI: 10.1126/science.272.5264.1026
Prev | Table of Contents | Next

Reports

Retinal Degeneration in Mice Lacking the gamma  Subunit of the Rod cGMP Phosphodiesterase

Stephen H. Tsang, Peter Gouras, Clyde K. Yamashita, Hild Kjeldbye, John Fisher, * Debora B. Farber, Stephen P. Goff dagger

The retinal cyclic guanosine 3',5'-monophosphate (cGMP) phosphodiesterase (PDE) is a key regulator of phototransduction in the vertebrate visual system. PDE consists of a catalytic core of alpha  and beta  subunits associated with two inhibitory gamma  subunits. A gene-targeting approach was used to disrupt the mouse PDEgamma gene. This mutation resulted in a rapid retinal degeneration resembling human retinitis pigmentosa. In homozygous mutant mice, reduced rather than increased PDE activity was apparent; the PDEalpha beta dimer was formed but lacked hydrolytic activity. Thus, the inhibitory gamma  subunit appears to be necessary for integrity of the photoreceptors and expression of PDE activity in vivo.

S. H. Tsang, J. Fisher, S. P. Goff, Howard Hughes Medical Institute, Department of Biochemistry and Molecular Biophysics, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA.
P. Gouras and H. Kjeldbye, Edward Harkness Eye Institute, Department of Ophthalmology, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA.
C. K. Yamashita and D. B. Farber, Jules Stein Eye Institute, Molecular Biology Institute and Department of Ophthalmology, UCLA School of Medicine, Los Angeles, CA 90095, USA.
* Present address: Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA.
dagger To whom correspondence should be addressed.


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Lessons from Photoreceptors: Turning Off G-Protein Signaling in Living Cells.
M. E. Burns and E. N. Pugh Jr. (2010)
Physiology 25, 72-84
   Abstract »    Full Text »    PDF »
The Leber congenital amaurosis protein, AIPL1, is needed for the viability and functioning of cone photoreceptor cells.
L. T. Kirschman, S. Kolandaivelu, J. M. Frederick, L. Dang, A. F.X. Goldberg, W. Baehr, and V. Ramamurthy (2010)
Hum. Mol. Genet. 19, 1076-1087
   Abstract »    Full Text »    PDF »
AIPL1, a Protein Associated with Childhood Blindness, Interacts with {alpha}-Subunit of Rod Phosphodiesterase (PDE6) and Is Essential for Its Proper Assembly.
S. Kolandaivelu, J. Huang, J. B. Hurley, and V. Ramamurthy (2009)
J. Biol. Chem. 284, 30853-30861
   Abstract »    Full Text »    PDF »
Characterization of a Canine Model of Autosomal Recessive Retinitis Pigmentosa due to a PDE6A Mutation.
N. Tuntivanich, S. J. Pittler, A. J. Fischer, G. Omar, M. Kiupel, A. Weber, S. Yao, J. P. Steibel, N. W. Khan, and S. M. Petersen-Jones (2009)
Invest. Ophthalmol. Vis. Sci. 50, 801-813
   Abstract »    Full Text »    PDF »
New mouse models for recessive retinitis pigmentosa caused by mutations in the Pde6a gene.
K. Sakamoto, M. McCluskey, T. G. Wensel, J. K. Naggert, and P. M. Nishina (2009)
Hum. Mol. Genet. 18, 178-192
   Abstract »    Full Text »    PDF »
Functional Rescue of Degenerating Photoreceptors in Mice Homozygous for a Hypomorphic cGMP Phosphodiesterase 6 b Allele (Pde6bH620Q).
R. J. Davis, J. Tosi, K. M. Janisch, J. M. Kasanuki, N.-K. Wang, J. Kong, I. Tsui, M. Cilluffo, M. L. Woodruff, G. L. Fain, et al. (2008)
Invest. Ophthalmol. Vis. Sci. 49, 5067-5076
   Abstract »    Full Text »    PDF »
Retinal Laminar Architecture in Human Retinitis Pigmentosa Caused by Rhodopsin Gene Mutations.
T. S. Aleman, A. V. Cideciyan, A. Sumaroka, E. A. M. Windsor, W. Herrera, D. A. White, S. Kaushal, A. Naidu, A. J. Roman, S. B. Schwartz, et al. (2008)
Invest. Ophthalmol. Vis. Sci. 49, 1580-1590
   Abstract »    Full Text »    PDF »
Intrinsically disordered {gamma}-subunit of cGMP phosphodiesterase encodes functionally relevant transient secondary and tertiary structure.
J. Song, L.-W. Guo, H. Muradov, N. O. Artemyev, A. E. Ruoho, and J. L. Markley (2008)
PNAS 105, 1505-1510
   Abstract »    Full Text »    PDF »
Removal of phosphorylation sites of {gamma} subunit of phosphodiesterase 6 alters rod light response.
S. H. Tsang, M. L. Woodruff, K. M. Janisch, M. C. Cilluffo, D. B. Farber, and G. L. Fain (2007)
J. Physiol. 579, 303-312
   Abstract »    Full Text »    PDF »
The Inhibitory {gamma} Subunit of the Rod cGMP Phosphodiesterase Binds the Catalytic Subunits in an Extended Linear Structure.
L.-W. Guo, H. Muradov, A. R. Hajipour, M. K. Sievert, N. O. Artemyev, and A. E. Ruoho (2006)
J. Biol. Chem. 281, 15412-15422
   Abstract »    Full Text »    PDF »
GAP-independent termination of photoreceptor light response by excess gamma subunit of the cGMP-phosphodiesterase..
S. H. Tsang, M. L. Woodruff, C.-K. Chen, C. Y. Yamashita, M. C. Cilluffo, A. L. Rao, D. B. Farber, and G. L. Fain (2006)
J. Neurosci. 26, 4472-4480
   Abstract »    Full Text »    PDF »
Ribozyme Knockdown of the {gamma}-Subunit of Rod cGMP Phosphodiesterase Alters the ERG and Retinal Morphology in Wild-Type Mice.
J. Liu, A. M. Timmers, A. S. Lewin, and W. W. Hauswirth (2005)
Invest. Ophthalmol. Vis. Sci. 46, 3836-3844
   Abstract »    Full Text »    PDF »
From the Cover: Leber congenital amaurosis linked to AIPL1: A mouse model reveals destabilization of cGMP phosphodiesterase.
V. Ramamurthy, G. A. Niemi, T. A. Reh, and J. B. Hurley (2004)
PNAS 101, 13897-13902
   Abstract »    Full Text »    PDF »
From the Cover: AIPL1, the protein that is defective in Leber congenital amaurosis, is essential for the biosynthesis of retinal rod cGMP phosphodiesterase.
X. Liu, O. V. Bulgakov, X.-H. Wen, M. L. Woodruff, B. Pawlyk, J. Yang, G. L. Fain, M. A. Sandberg, C. L. Makino, and T. Li (2004)
PNAS 101, 13903-13908
   Abstract »    Full Text »    PDF »
Functional Analysis of the Rod Photoreceptor cGMP Phosphodiesterase {alpha}-Subunit Gene Promoter: Nrl AND Crx ARE REQUIRED FOR FULL TRANSCRIPTIONAL ACTIVITY.
S. J. Pittler, Y. Zhang, S. Chen, A. J. Mears, D. J. Zack, Z. Ren, P. K. Swain, S. Yao, A. Swaroop, and J. B. White (2004)
J. Biol. Chem. 279, 19800-19807
   Abstract »    Full Text »    PDF »
Properties and Functions of GAF Domains in Cyclic Nucleotide Phosphodiesterases and Other Proteins.
R. Zoraghi, J. D. Corbin, and S. H. Francis (2004)
Mol. Pharmacol. 65, 267-278
   Full Text »    PDF »
Differential Expression of Rod Photoreceptor cGMP-Phosphodiesterase {alpha} and {beta} Subunits: mRNA AND PROTEIN LEVELS.
N. Piri, C. K. Yamashita, J. Shih, N. B. Akhmedov, and D. B. Farber (2003)
J. Biol. Chem. 278, 36999-37005
   Abstract »    Full Text »    PDF »
Muscle Expression of Human Retinol-binding Protein (RBP). SUPPRESSION OF THE VISUAL DEFECT OF RBP KNOCKOUT MICE.
L. Quadro, W. S. Blaner, L. Hamberger, R. N. Van Gelder, S. Vogel, R. Piantedosi, P. Gouras, V. Colantuoni, and M. E. Gottesman (2002)
J. Biol. Chem. 277, 30191-30197
   Abstract »    Full Text »    PDF »
Measurement of cytoplasmic calcium concentration in the rods of wild-type and transducin knock-out mice.
M. L Woodruff, A P Sampath, H. R Matthews, N V Krasnoperova, J Lem, and G. L Fain (2002)
J. Physiol. 542, 843-854
   Abstract »    Full Text »    PDF »
Soluble Guanylyl Cyclase Activator YC-1 Protects White Matter Axons from Nitric Oxide Toxicity and Metabolic Stress, Probably through Na+ Channel Inhibition.
G. Garthwaite, D. A. Goodwin, S. Neale, D. Riddall, and J. Garthwaite (2002)
Mol. Pharmacol. 61, 97-104
   Abstract »    Full Text »    PDF »
Sildenafil-Mediated Reduction in Retinal Function in Heterozygous Mice Lacking the {{gamma}}-Subunit of Phosphodiesterase.
D. Behn and M. J. Potter (2001)
Invest. Ophthalmol. Vis. Sci. 42, 523-527
   Abstract »    Full Text »
Molecular ophthalmology: an update on animal models for retinal degenerations and dystrophies.
F HAFEZI, C GRIMM, B C SIMMEN, A WENZEL, and C E REME (2000)
Br J Ophthalmol 84, 922-927
   Full Text »
Expression of Bcl-2 Protects against Photoreceptor Degeneration in retinal degeneration slow (rds) Mice.
I. Nir, W. Kedzierski, J. Chen, and G. H. Travis (2000)
J. Neurosci. 20, 2150-2154
   Abstract »    Full Text »    PDF »
A Point Mutation (W70A) in the Rod PDE{gamma} Gene Desensitizing and Delaying Murine Rod Photoreceptors.
D. J. Salchow, P. Gouras, K. Doi, S. P. Goff, E. Schwinger, and S. H. Tsang (1999)
Invest. Ophthalmol. Vis. Sci. 40, 3262-3267
   Abstract »    Full Text »    PDF »
Role for the Target Enzyme in Deactivation of Photoreceptor G Protein in Vivo.
S. H. Tsang, M. E. Burns, P. D. Calvert, P. Gouras, D. A. Baylor, S. P. Goff, and V. Y. Arshavsky (1998)
Science 282, 117-121
   Abstract »    Full Text »
Molecular Characterization of Human and Rat RGS 9L, a Novel Splice Variant Enriched in Dopamine Target Regions, and Chromosomal Localization of the RGS 9 Gene.
J. G. Granneman, Y. Zhai, Z. Zhu, M. J. Bannon, S. A. Burchett, C. J. Schmidt, R. Andrade, and J. Cooper (1998)
Mol. Pharmacol. 54, 687-694
   Abstract »    Full Text »
Stable and efficient gene transfer into the retina using an HIV-based lentiviral vector.
H. Miyoshi, M. Takahashi, F. H. Gage, and I. M. Verma (1997)
PNAS 94, 10319-10323
   Abstract »    Full Text »    PDF »
Strategems in Vitro for Gene Therapies Directed to Dominant Mutations.
S. Millington-Ward, B. O'Neill, G. Tuohy, N. Al-Jandal, A.-S. Kiang, P. F. Kenna, A. Palfi, P. Hayden, F. Mansergh, A. Kennan, et al. (1997)
Hum. Mol. Genet. 6, 1415-1426
   Abstract »    Full Text »    PDF »
Mouse models of human disease. Part II: recent progress and future directions..
M A Bedell, D A Largaespada, N A Jenkins, and N G Copeland (1997)
Genes & Dev. 11, 11-43
   PDF »
Mechanism of Transducin Activation of Frog Rod Photoreceptor Phosphodiesterase. ALLOSTERIC INTERACTIONS BETWEEN THE INHIBITORY gamma SUBUNIT AND THE NONCATALYTIC cGMP-BINDING SITES.
A. W. Norton, M. R. D'Amours, H. J. Grazio, T. L. Hebert, and R. H. Cote (2000)
J. Biol. Chem. 275, 38611-38619
   Abstract »    Full Text »    PDF »
The Catalytic and GAF Domains of the Rod cGMP Phosphodiesterase (PDE6) Heterodimer Are Regulated by Distinct Regions of Its Inhibitory gamma Subunit.
H. Mou and R. H. Cote (2001)
J. Biol. Chem. 276, 27527-27534
   Abstract »    Full Text »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)