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Candidate Gene Studies in Canine Progressive Retinal Atrophy
Digital Journal of Ophthalmology 1998
Volume 4, Number 3
August 30, 1998
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Gustavo D. Aguirre, M.D. | James A. Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, New York
Kunal Ray, MD | James A. Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University
Gregory M. Acland, MD | James A. Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University

Animal model, candidate gene, hereditary retinal degenerations
Hereditary diseases affecting the rods and cones, either primarily or secondary to RPE defects, are recognized in a number of different species including man. Regardless of the underlying cause, the diseases appear to affect the photoreceptors early and progressively; in the advanced stages, the entire visual cell layer is destroyed, and there is damage also to the inner retinal layers and the RPE. In man, this class of diseases is referred to, collectively, as retinitis pigmentosa (RP). Multiple loci for RP have been recognized, but few genes have been identified (see reference 1 and RetNet web page for review and updated summary). Recent studies in human patients and animal models of retinal degeneration have identified mutations in more than 6 different genes (e.g., rhodopsin [2], RDS/peripherin [3], rom-1 [4], a and ß subunits of rod cyclic GMP-phosphodiesterase {PDE6A [5] and PDE6B [6]}, and the cyclic GMP-gated channel a-subunit [7]) as being causally associated with RP. Some of these genes, e.g. rhodopsin, rom-1, PDE6B, are expressed exclusively in the rod photoreceptor cells, yet the clinical and pathologic phenotype of RP and related diseases indicates that there is progressive rod and cone degeneration with a late and secondary involvement of the RPE.

It appears that all defects that cause widespread disease and degeneration of rods, regardless of the selective expression of the gene product in rods, results in the concomitant loss of cones, and progressive retinal degenerative disease. The manner in which cellular dysfunction, disease and degeneration are expressed in the visual cell layer is dependent, to a large extent, on the gene affected and the nature of the mutation. However, different mutations of the same gene can result in a varied clinical phenotype, e.g. with opsin [8,9] and RDS/peripherin [10] genes, and factors external to the visual cell also may play a modulatory role to influence the temporal, topographic or cellular distribution of the disease.

Naturally occurring animal models of hereditary retinal degeneration are important to study retinal cell and molecular biology; of the known gene defects for autosomal RP in man, 2 (PDE6B [11,12] and RDS/peripherin [13]) have come initially FROM work done in animals. When the diseases represent mutations of unidentified gene loci, they illustrate unique mechanisms of photoreceptor dysfunction and degeneration, and provide insights INTO potential biochemical defects that can be pursued using a candidate gene approach. Identification of the mutant genes in animals, such as RDS/peripherin in mice [13], or abnormal ß subunit of cGMP-phosphodiesterase (PDE6B) in mice [11,14] and dogs [12,15], have led to identification of the homologous disorders in human patients [3,6], and the information generated FROM animal research can then be used to ANALYZE the expression of the mutant gene, or to devise strategies for the correction of the defect. Until recently, with the exception of rds in mice and of two feline diseases [16] which are dominantly inherited, every hereditary retinal degeneration reported in animal models has been autosomal recessive. Now we have identified the first case of an X-linked retinal degeneration in dogs [17]. The lack of animal models of X-linked retinal disease is particularly striking given the number of human retinal disorders mapped to the X chromosome [18].

Our laboratory has been involved in studies of hereditary retinal degeneration using the dog as a model. In the dog, these diseases are collectively referred to as progressive retinal atrophies (PRA), a term which, like RP in man, represents a grouping of DISTINCT genetic defects HAVING a broadly similar clinical phenotype. In comparison to other animal models of photoreceptor degeneration, the dog model offers some decided advantages, but also some limitations. These advantages have been discussed previously [19], and summarized here. Excluding man, more autosomal gene loci causing photoreceptor degeneration have been identified in dogs than in any other species. Moreover, the dog is the only animal in which X-linked retinal degeneration (XLPRA [17]), or a selective degeneration of cones that is homologous to congenital achromatopsia in man (cd [20]) has been identified (Table 1).
For cellular and functional studies, the dog retina has a significant population of cones which, except for the fovea, have a similar composition and distribution as the human. Lastly, the large size of the dog eye permits sampling different regions of the same eye sequentially in non-invasive studies or in terminal studies where different regions of the same retina can be examined morphologically, or the expression of different genes analyzed at the protein or mRNA level using tissue sections or tissue extracts.

The major limiting factor to the use of dogs in studies aimed at identifying genes and gene defects causing retinal degeneration is the inadequate density of the dog genetic map, and the lack of information on the synteny between dogs and the human and mouse maps; this prevents using the traditional positional cloning strategies which have been so successful in identifying retinal disease loci and genes in man. We have partly circumvented these limitations by developing very extensive informative pedigrees (refer to Figure 1 of reference 21) that can be used for candidate gene testing by linkage analysis, and sufficient retinal tissue at a pre-degenerate stage has been obtained FROM the different disease models in ORDER to isolate mRNAs for differential display or subtraction methods to identify candidate sequences that can be further tested in the informative pedigrees.

The limitations of working on a genome "poor" species such as the dog are presently being overcome by several research groups who are in the process of developing a canine genetic map based on microsatellites and anchor loci. The relevant web sites are listed in the footnote belowb.

Not surprisingly, there is conservation of synteny between regions of the dog map with that of the mouse and human. This has allowed us to establish linkage between microsatellite markers and/or gene loci to 3 of the primary photoreceptor diseases grouped under the progressive retinal atrophy rubric, and establishing the chromosomal localization of the locus (erd, prcd, rcd2). For one of these diseases, early retinal degeneration (erd), three microsatellite markers were identified recently that demonstrated significant linkage to each other and to the erd locus; one of these markers is known to be internal to the canine von Willebrand factor gene. In addition, each of these 3 microsatellites, as well as the canine K-RAS gene, was shown to map uniquely to the same rodent/canine somatic cell hybrid line (E. Ostrander, personal communication). Based on the linkage and physical mapping work to date, it appears that erd maps to the canine chromosomal region corresponding to human chromosome 12p, and the distal region of mouse chromosome 6. This is a region with no previously identified retinal degeneration loci [22].

In this review, we will present a brief overview of PRA in the dog, and the specific genetic disorders known to occur in this GROUP of diseases. In addition, we will summarize the results of the candidate gene studies that have been carried out to identify the molecular basis of some of these diseases.

Progressive Retinal Atrophy (PRA)
The PRA class of diseases represents a GROUP of genetically different retinal disorders HAVING similar disease phenotype. All SHOW the same general ophthalmoscopic abnormalities, and visual deficits characterized initially by rod dysfunction followed by loss of day vision; in the late stages of the disease the animals are blind, have end-stage retinal degenerative changes, and secondary cataracts. The clinical phenotype of PRA in dogs is similar to RP in man.

Progressive retinal atrophy is subdivided INTO developmental and degenerative diseases (Table 2). The developmental class represents a large aggregate of genetically DISTINCT disorders which are expressed cytologically in the postnatal period, at the time that visual cells are beginning to differentiate. These developmental disorders represent a dysplasia of the rod and/or cone photoreceptors, and each has its own unique disease course and phenotype as assessed by functional and morphologic criteria [23-26]. Even though all dysplasias SHOW rather severe structural alterations of the photoreceptor cells, the rate of progression to loss of cones, the benchmark criteria for loss of functional vision, is varied; e.g., this occurs early in the erd, rcd1 and rcd2 retinas, but not until the equivalent of middle age in pd and rd (Table 2).

In contrast, the degenerative class of diseases represent defects in photoreceptor maintenance, where the visual cells degenerate after HAVING differentiated normally-this class includes diseases at the progressive rod-cone degeneration (prcd) [27,28] and XLPRA [17] gene loci. Here, disease occurs more slowly, and is modified by temporal and topographic factors. Different alleles have been identified at the prcd locus [28], and these segregate independently to regulate the rate, but not the phenotype, of photoreceptor degeneration (Acland and Aguirre, unpublished).

Candidate Gene Studies

Those genes which code for proteins that are expressed exclusively or predominantly in the photoreceptor cells, or which are involved in biochemical pathways known to be abnormal in a hereditary retinal degeneration, are considered as candidate genes for the diseases. Using such an approach, mutations in several genes, e.g. rhodopsin, RDS/peripherin, rom-1, a and ß subunits of rod cyclic GMP-phosphodiesterase (PDE6A and PDE6B), the cyclic GMP-gated channel, guanylate cyclase and the ABC transporter protein, have been shown to be causally associated with retinal diseases, particularly RP and allied retinal disorders in man.

In ORDER to carry out the candidate gene studies in dogs, however, it has been necessary to clone the canine specific genes and/or cDNAs, sequence the exon flanking regions to scan for mutations in the coding regions using conformational sensitive gel electrophoresis techniques, or identify intragenic polymorphisms or repeat elements useful for linkage analysis. In our lab, we have cloned the canine specific genes for many of the photoreceptor-specific or phototransduction proteins (RDS/peripherin [29], transducin a1 [30], PDE6A [31] and PDE6G [32], and the rod cyclic GMP-gated channel protein a subunit [33]). Other groups in the US, Germany, Finland and England have cloned most of the remaining canine-specific candidates for genes involved in the activation and de-activation phases of phototransduction or expressed in the photoreceptor cells (e.g., rom-1, rhodopsin, rod transducin-b and -g, cone transducin-b, arrestin, and phosducin), and these sequences have been deposited in GenBank. With this information, it is now possible to examine these candidate genes to determine if they are causally associated with any of the forms of canine PRA.

The best example of a candidate gene approach to examine disease causing mutations in photoreceptor specific genes in the dog is rod-cone dysplasia1 (rcd1) in the Irish setter. This is a recessively inherited photoreceptor dysplasia characterized by arrested differentiation of visual cells resulting FROM abnormal retinal cGMP metabolism [34,35]. Beginning at 10 days of age, deficient cyclic GMP-phosphodiesterase (cGMP-PDE) activity causes the retinal levels of cyclic GMP to rise sharply to concentrations up to 10-fold higher than normal; these biochemical abnormalities are present before degenerative changes are observed in the photoreceptor cells. The morphologic and biochemical phenotype of the disease is similar to that present in the rd mouse [36].

Once the ß-subunit of cGMP-PDE was identified as defective in rd [11] and 2 different abnormalities established in all rd strains [14,37], we focused on this gene as a candidate for the rcd1 defect. Together with Debora Farber's group, we detected altered expression of PDE6B mRNA very early during development [15,38]; subsequently, two independent groups confirmed that PDE6B indeed was defective in the disease, and identified a mutation in codon 807 (Trp807x) which presumably results in the premature termination of the PDE6B protein by 49 amino acid residues [12,39]. Recent studies in our lab have demonstrated that the codon 807 mutation is the only defect present in rcd1 affected dogs, either those maintained in our research colony, or in the general population [21]. This mutation has now been excluded FROM the various forms of PRA present in over 20 different breeds of dogs [21,39,40].

However, a candidate gene approach is not always a more efficient strategy to identify the gene and disease causing mutation responsible for the disease. For example, our laboratory has worked on another recessively inherited retinal degeneration found in collies which has been termed rod-cone dysplasia 2 (rcd2) [41] to differentiate it FROM the disease present in the Irish setter dogs. Based on clinical, electrophysiological, morphological, and biochemical criteria, the two diseases are identical; these similarities have been previously reviewed [19]. In both, there is an equally rapid increase in retinal cGMP levels early in the postnatal period, and the magnitude of this elevation, as well as its time course, are very similar. In both rcd1 and rcd2 there is deficient cGMP-PDE activity, although in the latter the activity is calmodulin independent [42].

Although rcd1 and rcd2 are phenotypically and biochemically identical, there is considerable evidence that the disorders represent mutations of different genes. With the advent of a molecular diagnosis for rcd1, we have established that this mutation is not present in rcd2, and that the nucleotide sequence of exon 21 of the PDE6B gene in affected collies is the same as in normal controls [21]. The most compelling evidence for non-identity of the two diseases comes FROM previous work carried out by our GROUP which performed crosses between dogs affected with rcd1 and rcd2, and found the progeny to be normal using functional, structural and biochemical methods of analyses [25]. Thus rcd1 and rcd2 represent non-allelic diseases which have similar effects on retinal cyclic GMP metabolism. Based on biochemical studies, it is likely that the molecular defect in rcd2 resides in one of the 2 other PDE subunits, or in a gene coding for a protein involved in PDE activation. However, studies by Wang and others in our laboratory have excluded, at least on a preliminary basis, several of these candidate genes (e.g., transducin-a1 [30], PDE6A [43], PDE6G [43]) which, if defective, presumably would result in the observed abnormality in cGMP metabolism in the visual cells.

Of the degenerative GROUP of hereditary retinal diseases, mutations at the prcd gene locus account for all of the autosomal disorders recognized to date [28,44]. The prcd gene and the different mutations responsible for the defined allelic variants have yet to be identified. However, recent studies in our lab have excluded opsin [45], transducin a-1 [30], PDE6B [46], and RDS/peripherin [29] as being causally associated with the disease. Because we have been able to generate pedigrees that are informative for both the prcd and erd mutations, the parallel studies in erd also have excluded transducin añ1 [30], RDS/peripherin [29], and PDE6B [25]. Based on our recent linkage studies which localize the erd locus to a region homologous to human chromosome 12p, the lack of success with the candidate gene approach in erd is not surprising [22]. After all, no previously identified retinal degeneration loci, or immediately obvious candidate loci, have been mapped to this region, suggesting that erd may be a novel retinal degeneration locus.

The current status of the candidate gene studies for the different forms of PRA and other inherited photoreceptor degenerations in the dog is summarized in TABLE 2. Where possible, exclusion of a candidate gene has been done using linkage or breeding studies (to examine for non-allelism), since these approaches provide the most conclusive proof for lack of association of a gene with a retinal disease locus. However, in some cases disease-informative pedigrees are not available for the diseases, or, in others, polymorphisms in a candidate gene are not identified in the pedigree which is informative for the disease of interest. To that end, we have had to resort to genomic and/ or cDNA sequencing, exon scanning, or searching for mutations in RT-PCR products of retinal mRNA by sequencing or using conformational sensitive gel electrophoresis methods. Details of these results are provided in the references cited in TABLE 2.

The variety of different primary diseases affecting the retinal photoreceptors of dogs makes this species ideally suited for studies of retinal disease mechanisms and examination of genotype and phenotype correlation. Candidate gene studies indicate that most if not all of these diseases are caused by defects in genes not yet associated with human retinal degenerative disorders. These defects may be in genes not yet identified, but located in the many loci to which retinal diseases have been mapped. Alternatively, they may represent diseases caused by defects in genes not previously suspected to play a critical role in photoreceptor function, maintenance or viability. With the help of the developing canine genome map, it will be possible to localize many of these genes to a chromosomal position and determine the homologous region in the human or mouse genome maps. Once this occurs, the full potential that the canine models have for retinal disease research will be fulfilled.
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14. Pittler SJ., Baehr W., Identification of a nonsense mutation in the rod photoreceptor cGMP phosphodiesterase ß-subunit gene of the rd mouse. Proc Natl Acad Sci 88:8322-8326 (1991)

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18. Rosenfeld PJ., McKusick VA., Amberger JS., Dryja TP., Recent advances in the gene map of inherited eye disorders: primary hereditary diseases of the retina, choroid and vitreous. J Med Genet 31:903-915 (1994)

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20. Gropp, KE., Szél, Á., Huang, JC., Acland, GM., Farber, DB., Aguirre, GD., Selective absence of cone outer segment ß3-transducin immunoreactivity in hereditary cone degeneration (cd). Exp. Eye Res. 63:285-296 (1996)

21. Ray, K., Baldwin, VJ., Acland, GM., Blanton, SH., Aguirre, GD., Co-segregation of codon 807 mutation of the rod cGMP phosphodiesterase b- gene (PDEB) and rcd1. Investigative Ophthalmology and Visual Sciences 35: 4291-4299 (1994)

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28. Aguirre GD., Acland GM., Variation in retinal degeneration phenotype inherited at the prcd locus. Exp Eye Res 46:663-687 (1988)

29. Ray, K., Acland, GM., and Aguirre, GD., Nonallelism of erd and prcd and exclusion of the canine RDS/peripherin gene as a candidate for both retinal degeneration loci; Investigative Ophthalmology and Visual Sciences 37: 783-794 (1996)

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"Cloned and/or Mapped Genes Causing Retinal Degeneration or Related Diseases"
RetNet Retinal Information Network of The Laboratory for the Molecular Diagnosis of Inherited Eye Disease, The University of Texas Health Science Center, Houston.

Dog Genome Project
University of California at Berkeley
Fred Huchinson Cancer Research Center
PRA Homepage

Table 1: Primary Hereditary Diseases of the RPE-Photoreceptor
Complex in Animal Models*


Disease name, gene or gene locus

Mouse rd, rds, pcd, nr, rd-3, mnd, mivit
Cat pd, rcd, prcd
Dog cd, csnb, rcd1, rcd2, rd, erd, pd, rdi, prcd, XLPRA
Chicken rd, rdd, DAM

* modified FROM Aguirre, 1996. This TABLE also includes diseases which serve as models for vitiligo and ocular depigmentation (DAM, mivit), selective cone degeneration (cd), and congenital stationary nightblindness (csnb).

For cellular and functional studies, the dog
retina has a significant population of cones which, except for the fovea,
have a similar composition and distribution as the human. Lastly, the large size of the dog eye permits sampling different regions of the same eye sequentially in non-invasive studies or in terminal studies where different regions of the same retina can be examined morphologically, or the expression of different genes analyzed at the protein or mRNA level using tissue sections or tissue extracts.

Table 2: Progressive retinal atrophy gene loci
Abnormal photoreceptor development
Breed Disease name Gene locus Gene excluded or included References        
Irish setter rod-cone dysplasia 1 rcd1 PDE6B defect 12, 15, 21, 25, 34, 35, 39, 40        
Collie rod-cone dysplasia 2 rcd2 Transducin a-1, PDE6A, PDE6B, PDE6G 25, 30, 41, 42, 43        
Norwegian elkhound rod dysplasia rd        
early retinal degeneration erd Transducin a-1, RDS/peripherin, opsin, PDE6B 22, 24, 25, 29, 30        
Miniature schnauzer photoreceptor dysplasia pd not done 26        
Photoreceptor degeneration
Breed Disease name Gene locus Gene excluded or included References        
Miniature poodle; American and English cocker spaniels; Labrador retriever;
Portuguese water dog
progressive rod-cone degeneration prcd Transducin a-1, RDS/peripherin, opsin, PDE6B 27, 28, 29, 30, 44, 45, 46        
Siberian husky X-linked PRA XLPRA not done 17