Genetic and phenotypic variations of inherited retinal diseases in dogs: the power of within- and across-breed studies

Abstract

Considerable clinical and molecular variations have been known in retinal blinding diseases in man and also in dogs. Different forms of retinal diseases occur in specific breed(s) caused by mutations segregating within each isolated breeding population. While molecular studies to find genes and mutations underlying retinal diseases in dogs have benefited largely from the phenotypic and genetic uniformity within a breed, within- and across-breed variations have often played a key role in elucidating the molecular basis. The increasing knowledge of phenotypic, allelic, and genetic heterogeneities in canine retinal degeneration has shown that the overall picture is rather more complicated than initially thought. Over the past 20 years, various approaches have been developed and tested to search for genes and mutations underlying genetic traits in dogs, depending on the availability of genetic tools and sample resources. Candidate gene, linkage analysis, and genome-wide association studies have so far identified 24 mutations in 18 genes underlying retinal diseases in at least 58 dog breeds. Many of these genes have been associated with retinal diseases in humans, thus providing opportunities to study the role in pathogenesis and in normal vision. Application in therapeutic interventions such as gene therapy has proven successful initially in a naturally occurring dog model followed by trials in human patients. Other genes whose human homologs have not been associated with retinal diseases are potential candidates to explain equivalent human diseases and contribute to the understanding of their function in vision.

Fig. 1

Accumulation of the numbers of mapped loci (light gray) and identified genes (dark gray) in human RDs from 1980 to 2011. Reprinted from RetNet, http://www.sph.uth.tmc.edu/RetNet, with permission (Stephen P. Daiger, PhD, and the University of Texas Health Science Center at Houston)

Fig. 2

The structural and functional elements of the retina and the localization of selected genes involved in canine retinal degeneration. a Histologic section of the canine retina showing the highly ordered lamination from the outer (top) to the inner (bottom) retina. The rod and cone photoreceptors that form the outermost layer receive the light stimuli and are nourished by the retinal pigment epithelium (RPE). The outer nuclear layer (ONL) contains the nuclei and cell bodies of the photoreceptors. The inner nuclear layer (INL) contains the nuclei of the secondary neurons (i.e., bipolar, amacrine, and horizontal cells) and the glial Müller cells. The innermost ganglion cell layer (GCL) receives the input from photoreceptors via the bipolar and amacrine cells and transmit the signals to the brain. b Localization of selected genes associated with RDs in dogs. *Indicates the cone photoreceptors. Canine RD genes with unknown retinal localization or ubiquitous expression are not displayed. OS outer segment, IS inner segment. c The retinoid cycle recycles the light-absorbing chromophore. Absorption of a photon (hv) converts 11-cis-retinal bound to opsin (Rho) into all-trans-retinal initiating phototransduction. All-trans-retinal is reduced by photoreceptor retinol dehydrogenase (RDH) to all-trans-retinol and exported to the RPE where it is esterified by lecithin retinol acyltransferase (LRAT), converted to 11-cis-retinol by RPE65, and oxidized to 11-cis-retinal by NAD and a cis-specific retinol dehydrogenase (cis-RDH). 11-cis-retinal is exported back to the OS to again bind to opsin. CRALBP cellular retinaldehyde-binding protein, CRBP cellular retinol-binding protein, IRBP interphotoreceptor matrix retinoid-binding protein. d The phototransduction cascade converts light stimuli to electrical signal. Activated opsin (R*) in the disk membrane activates transducin (G) to G* which in turn activates phosphodies-terase (PDE) to PDE**. PDE** hydrolyzes cGMP, reducing its cytoplasmic concentration which results in closure of cGMP-gated channels in the plasma membrane. This causes hyperpolarization of the photoreceptors leading to signals sent to the downstream neurons. The schematics are modified and reprinted with permission from John Wiley and Sons (Nawrot et al. 2006) (c) and Elsevier Limited (Leskov et al. 2000; Pugh 1999) (d)

Fig. 3

ERG of dogs affected with PRA and CRD. Rod, rod/cone, and cone ERG recordings obtained by dark-adapted responses to blue, red, and white flashes, respectively. Rod and cone flicker recordings were obtained by low- (5 Hz) and high-intensity [5 Hz (a), 30 Hz (b)] white flashes, respectively. Onset of stimuli for the rod and cone flicker responses are indicated by the upward deflection of square wave pulses below the responses (a) or short vertical arrows under the responses (b). a Absence of rod responses with subsequent and progressive deterioration of the cone function in a Norwegian elkhound affected with rd (reprinted from Aguirre 1978). b Cone dysfunction detected by 1.2 years, followed by further deterioration of both cone and rod function in Glen of Imaal terrier dogs affected with crd3. At all ages, the loss of cone function is more prominent than that for rods (reprinted with permission from Goldstein et al. 2010c)

Fig. 4

Discovery approaches for canine RD loci and genes. The cumulative numbers of loci and mutations identified as causing canine RD are shown, classified according to the discovery approach used. Note that the chromosomal location and the mutation were reported concurrently for cd, cord1, osd1, and osd2. The disease symbols correspond to those shown in Table 1

Fig. 5

Diverse breeds share a common identical-by-descent mutation in PRCD. Genetic diversity of 17 of 22 dog breeds that segregate the C2Y mutation in PRCD is shown in a neighbor-joining tree of domestic dogs and gray wolves (reprinted and modified with permission from Vonholdt et al. 2010). The names of breeds that were included in the study by Vonholdt et al. (2010) are outlined. For other breeds, images are placed at a hypothetical position based on breed history and previously reported structural analysis of canine breeds (Parker et al. 2004). Dog images are from Wikipedia (http://en.wikipedia.org/) and not to scale