Involvement of cyclic GMP phosphodiesterase activator in an hereditary retinal degeneration

Liu, Y. P.; Krishna, Gopal; Aguirre, Gustavo D.; Chader, Gerald J.

doi:10.1038/280062a0

Cited by 41 publications

(9 citation statements)

References 22 publications

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“…The Rcd1 dog carries a (2420G>A) nonsense mutation in the C-terminus of the PDE6β subunit 30 leading to truncation and destabilization of the gene product and a nonfunctional PDE6 holoenzyme. 31,32 Retinal development is normal in affected dogs until 13 days of age, at which point photoreceptor development is arrested. Rod degeneration then occurs gradually from 1 to 5 months of age, followed by cone loss within 1 to 2 years.…”

Section: Introductionmentioning

confidence: 99%

Restoration of Vision in the pde6β-deficient Dog, a Large Animal Model of Rod-cone Dystrophy

et al. 2012

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Section: Introductionmentioning

confidence: 99%

Restoration of Vision in the pde6β-deficient Dog, a Large Animal Model of Rod-cone Dystrophy

et al. 2012

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“…The early onset of the photoreceptor degeneration has been well defined by morphological and biochemical studies (2)(3)(4). Clin-ically, the disorder is grouped within a famnily of related canine retinal degenerations which are termed progressive retinal atrophies (5).…”

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confidence: 99%

“…The earliest known biochemical manifestation of the rcdl phenotype is a rapid accumulation of cGMP to levels that are about 10-fold above those of age-matched controls (2)(3)(4)8). These features are reminiscent of the phenotype seen in the rd mouse in which a nonsense mutation in exon 7 ofthe cGMP phosphodiesterase (PDE) (-subunit gene prevents the formation of a functional enzyme (9) leading to elevated cGMP levels and a rapid rod photoreceptor degeneration.…”

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confidence: 99%

Irish setter dogs affected with rod/cone dysplasia contain a nonsense mutation in the rod cGMP phosphodiesterase beta-subunit gene.

Suber

Pittler

Qin

et al. 1993

Proc. Natl. Acad. Sci. U.S.A.

260

127

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Irish setter dogs affected with a rod/cone dysplasia (locus designation, rcdl) display markedly elevated levels of retinal cGMP during postnatal development. The photoreceptor degeneration commences =25 days after birth and culminates at about 1 year when the population of rods and cones is depleted. A histone-sensitive retinal cGMP phospho- subunit by 49 residues, thus removing the C-terminal domain that is required for posttranslational processing and membrane association. These results suggest that the redl gene encodes the rod photoreceptor PDE 13 subunit and that a nonsense mutation in this gene is responsible for the production of a nonfunctional rod PDE and the photoreceptor degeneration in the rcdl/rcdl Irish setter dogs.The Irish setter rod/cone dysplasia leading to a rapidly progressing loss of photoreceptors (1) is inherited as an autosomal recessive trait (genetic locus, rcdl). The early onset of the photoreceptor degeneration has been well defined by morphological and biochemical studies (2-4). Clin-ically, the disorder is grouped within a famnily of related canine retinal degenerations which are termed progressive retinal atrophies (5). In affected dogs, retina and photoreceptor development appears normal until 13 days of age (4), but subsequent development of rod photoreceptor cells is arrested. Rod photoreceptor degeneration is evident by 1 month of age; nearly all of the rod photoreceptors have degenerated by 5 months, and cone photoreceptor degeneration is completed by about 1 year (for review, see refs. 6 and 7).The earliest known biochemical manifestation of the rcdl phenotype is a rapid accumulation of cGMP to levels that are about 10-fold above those of age-matched controls (2-4, 8). These features are reminiscent of the phenotype seen in the rd mouse in which a nonsense mutation in exon 7 ofthe cGMP phosphodiesterase (PDE) (-subunit gene prevents the formation of a functional enzyme (9) leading to elevated cGMP levels and a rapid rod photoreceptor degeneration. Earlier studies of retinas from normal and affected Irish setters showed that the a and 'y mRNAs of affected dog PDE were of normal size and abundance (10), whereas the /-subunit mRNA level appeared to be reduced (11,12). This finding, similar to that in the rd mouse, suggests a defect in the dog PDE l3-subunit gene. Since a previous study showed the presence of a histone sensitive cGMP PDE activity in affected, immature Irish setter retinas (13), we reinvestigated its origin by an HPLC method which is capable of separating rod and cone PDEs (14). In this paper we identify the residual PDE activity in affected Irish setter retinas as comigrating with cone PDE, whereas rod PDE activity is completely absent. We further provide evidence that a functional /3 subunit is not produced in affected retinas and that a nonsense mutation near the C-terminal end of the /-subunit gene leads to truncation and destabilization of the gene product,

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“…In the Purkinje cell degeneration (pcd) mutant mouse, the photoreceptor cells are also affected (Mullen and LaVail, 1975;Mullen et al, 1976). In the mouse, a pathological increase in cyclic nucleotide concentration has been observed in both cerebellar and photoreceptor cell dystrophies (Farber and Lolley, 1974;Liu et al, 1979;Spinka et al, 1980;Ghetti et al, 1981). Furthermore, in some human neurological syndromes such as olivopontocerebellar atrophy type 111, typical histopathological findings include retinal degeneration primarily involving the photoreceptor cell layer (Traboulsi et al, 1988;Dooley et al, 1992).…”

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confidence: 99%

Distribution of Purkinje cell‐specific Zebrin‐II/aldolase C immunoreactivity in the mouse, rat, rabbit, and human retina

Caffé

Schantz

Szél

et al. 1994

J of Comparative Neurology

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The developmental, genetic, and biochemical similarities that have been observed between the cerebellum and retina form the basis for ongoing investigations into retinal expression of cerebellar-specific proteins. We have examined the mouse, rat, rabbit, and human retina for expression of a protein that is present in parasagittal Purkinje cell strips and that is recognized by the antibody Zebrin-II. This protein has recently been identified as a member of the aldolase C isoenzymes. Western blotting and immunocytochemistry have been used. The monoclonal antibody Zebrin-II recognized a prominent 36 kDa protein band on immunoblots of both the cerebellum and the retina of the examined species. Immunocytochemistry showed that, in the three nonhuman species, cells were stained in the ganglion cell layer (GCL). In addition, in the mouse and rabbit, cells in the inner nuclear layer (INL) were also labeled. Except for the visual streak, there were more immunopositive cells in the rabbit GCL and INL than in corresponding areas of the mouse retina. In the human, in contrast to the other species, the photoreceptor cell layer was strongly aldolase C immunoreactive. In all species except for the rat, the photoreceptor inner segments also displayed a weak labeling. The results show that this aldolase C isoenzyme is another protein that is selectively expressed by the cerebellum and retina. Furthermore, the retinal expression is species specific, and this pattern seems to show a good correlation with the oxygenation level of the individual compartments. The indication that this aldolase C isoenzyme has specific developmental functions in the retina provides additional clues for our understanding of cerebellar organization.

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Involvement of cyclic GMP phosphodiesterase activator in an hereditary retinal degeneration

Cited by 41 publications

References 22 publications

Restoration of Vision in the pde6β-deficient Dog, a Large Animal Model of Rod-cone Dystrophy

Restoration of Vision in the pde6β-deficient Dog, a Large Animal Model of Rod-cone Dystrophy

Irish setter dogs affected with rod/cone dysplasia contain a nonsense mutation in the rod cGMP phosphodiesterase beta-subunit gene.

Distribution of Purkinje cell‐specific Zebrin‐II/aldolase C immunoreactivity in the mouse, rat, rabbit, and human retina

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