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

Abstract

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,

The Rod cGMP-phosphodiesterase β-Subunit Promoter Is a Specific Target for Sp4 and Is Not Activated by Other Sp Proteins or CRX

“…The gene encoding the ␤-subunit of the human enzyme (␤-PDE) 1 has been well characterized and consists of 22 exons encompassing ϳ43 kb of genomic DNA (2). Genetic defects in this gene have been linked to retinal degeneration in several animal species and human (3)(4)(5)(6)(7)(8)(9). There is increasing evidence that abnormalities in transcriptional regulatory components of different genes contribute significantly to or directly cause pathological phenotypes in the retina (10 -13).…”

Nrl and Sp Nuclear Proteins Mediate Transcription of Rod-specific cGMP-phosphodiesterase β-Subunit Gene

“…Mutations in the ␤-subunit of cGMP-PDE (␤-PDE) are currently the most common known cause of autosomal recessive retinitis pigmentosa (3). In addition, mutations in the ␤-PDE gene result in congenital stationary night blindness (4) and retinal degeneration in animal models (5)(6)(7)(8). Recently, genetic defects in transcription mechanisms that control the expression of several retina-specific genes have been linked to different types of retinal disorders (9 -12).…”

Analysis of PDE6D and PDE6G genes for generalised progressive retinal atrophy (gPRA) mutations in dogs

“…The DNA of 22 dog breeds including 114 gPRA-affected animals are covered in this study. For six of these breeds either the causative gPRA mutations (Irish Setter [31], and Sloughi [12]) or linked markers for the progressive rod cone degeneration (prcd) form of gPRA are already known (Australian Cattle Dog, English Cocker Spaniel, Labrador Retriever, Miniature Poodle; patented by OptiGen, USA). The PDE6G gene is located near the prcd region, but is excluded as a cause for RP 17 in man [4], the homologous gPRA form in these breeds [1].…”

“…For autosomal recessively transmitted (ar), generalised progressive retinal atrophy (gPRA), the most common hereditary form in dogs, mutations have been identified in the β subunit of the PDE (PDE6B) gene in Irish Setters and Sloughis [12,31] and in the α subunit (PDE6A) gene in Cardigan Welsh Corgis [25].…”