Animal models of SIMON M. PETERSEN-JONES human retinal dystrophies

Abstract retinal dystrophies in man occur as part of multi system diseases or syndromes such as Usher's Naturally occurring retinal dystrophies in syndrome and Norrie disease. There are animal laboratory and companion animals represent a models with similar multi-system involvement, wealth of different conditions, some of which one example being the tubby mouse (tub) that are important from a comparative point of develops a syndromic disease characterised by view, and all of which offer opportunities to retinal and cochlear degeneration as well as further the understanding of retinal function adult-onset obesity with insulin resistance and and reaction in health and disease. The study impaired glucose tolerance.1 Identification of of animal models of retinal dystrophies has the tub gene led to the recognition of a new provided candidate genes for investigation in family of genes, the human homologues of conditions of man such as retinitis pigmentosa which are potential candidates for retinal and has also led to the identification of new dystrophies? There are still several naturally genes and even new families of genes. occurring mouse models of retinal dystrophy Mutations in the gene for the beta subunit of that await molecular characterisation and may cyclic GMP phosphodiesterase cause retinal provide new candidate genes for human disease dystrophies in man, mice and dog, and or, as was the case with the tubby mouse, lead mutations in the gene for the structural protein to the identification of new families of genes. In peripherin/RDS result in a retinal dystrophy addition to the spontaneous dystrophies the in the mouse and a spectrum of differing laboratory mouse offers the opportunity for retinal dystrophies in man. Animals with genetic manipulation either by the introduction homologous retinal dystrophies to man may of a foreign gene (to create a transgenic animal) make useful models for investigation of treatment either by drugs or by gene therapy. or by the targeted disruption of an endogenous Furthermore the use of transgenics and gene gene (gene 'knock-out'). These techniques are targeting in laboratory mice offers the powerful tools for the investigation of the opportunity to create new models of human retinal dystrophies as well as other diseases. retinal dystrophies and also to investigate the Naturally occurring retinal dystrophies are effect of gene dysfunction. recognised in other laboratory animals, for example the Royal College of Surgeons (RCS)

Key words Animal model, cGMP rat which has been studied in detail, although phosphodiesterase, Peripherin / RDS; the responsible gene mutation currently Progressive retinal atrophy, Retinal dystrophy; remains elusive. Retinitis pigmentosa Companion animals, particularly dogs, represent a diverse source of different models of retinal dystrophies. The most important group Retinal dystrophies affect a number of different of conditions are the generalised progressive animal species and are well recognised in retinal atrophies (PRAs) (for a review see laboratory and companion animals. There are Petersen-Jones3). These inherited conditions all conditions of several species that mirror result in a progressive photoreceptor-led retinal conditions in man such as retinitis pigmentosa. degeneration resulting in similar clinical and Identification of the gene defects responsible for ophthalmoscopic signs, but with varying ages at two such mouse models of retinal dystrophy - onset and rates of progression. Those forms that dJ the retinal degeneration (rd, rdl or pdeb' ) have been studied in detail can be divided into S.M. Petersen-Jones � mouse and the retinal degeneration slow (rds, photoreceptor dysplasias or photoreceptor Department of Small Animal dZ Clinical Sciences rd2 or prph2, ) mouse - led to the screening of degenerations. With the dysplasias the College of Veterinary the same genes (the beta subunit of cyclic GMP photoreceptor development is abnormal or Medicine phosphodiesterase and peripherin/RDS becomes halted in the immediate postnatal Michigan State University respectively) in patients with retinal period when retinal maturation normally East Lansing MI48824-1314, USA dystrophies and resulted in the identification of occurs. The dysplastic photo receptors then Fax: +1 (517) 355-5164 a number of causal gene mutations. Some progressively degenerate. With those forms of

566 Eye (1998) 12, 566-570 © 1998 Royal College of Ophthalmologists PRA classified as degenerations the photoreceptors Retinal dystrophies of known genetic cause appear to attain normal adult conformation but The genetic causes of a number of retinal dystrophies subsequently progressively degenerate. PRA has been have been identified in man and fewer have been described in over 100 different breeds of dog, only a identified in animals. The following gives two examples small number of which have been studied in detail. where gene defects that are known to cause retinal Despite this, the breeding studies that have been dystrophies in man are also known to cause retinal performed have shown that there are several distinct dystrophies in animals. No doubt as further molecular forms of PRA. The majority of canine PRAs are studies of animal and human retinal dystrophies are recessively inherited although an X-linked form has been performed more animal homologues of human disease recognised in the Siberian husky and is the only animal will be identified. model of X-linked retinitis pigmentosa.4 One form, a progressive rod-cone degeneration (prcd), is present as an allelic condition in several breeds (miniature and toy poodle, English and American cocker spaniel, Labrador Cyclic GMP phosphodiesterase beta subunit (PDEj3) retriever and Portuguese water dog). Although the prcd mutations gene has not been identified, recently genetic linkage to The gene for PDEI), which encodes a member of the the locus was described.s Rod-cone dysplasia type one visual transduction cascade, is known to be mutated in (redl) in the Irish setter remains the only form of retinal dystrophies of man, mouse and dog. The first companion animal PRA for which the gene mutation has discovery of a mutation in these gene was in the retinal been identified (see Note added in proof). The mutation degeneration (rd) mouse. The rd mouse has a very early is in the cGMP phosphodiesterase beta subunit gene onset of photoreceptor disease. Photoreceptors develop (PDEI)). The same gene is mutated in the rd mouse and until about 10 days of age and then go on to degenerate also in some forms of retinitis pigmentosa as described in rapidly such that by 20 days of age most photoreceptors more detail in the following section. are lost (with the exception of some cones).16 Studies PRA is less common in the cat than the dog. Two have shown that there are elevations in retinal cGMP forms have been recognised and investigated in the levels prior to retinal degeneration,17 and that this is Abyssinian cat. One form, which has a very early onset associated with lowered cGMP phosphodiesterase and rapid progression, is dominantly inherited and is the activity.1S The defective gene was identified by Bowes et only companion animal model of autosomal dominant 1Y al. using a cDNA subtractive technique coupled with retinitis pigmentosa. The second form is recessively differential hybridisation?O,21 Two mutations were found inherited and has a later onset of a slow, progressive in the rd PDEI) gene. One is a nonsense mutation at rod-cone degeneration. This second form has similarities codon 34722 that introduces a stop codon; the second is a to prcd in the poodle. retroviral element inserted in intron 1.23 Both mutations As well as PRA the dog also suffers from another have been found in all strains of rd mice. Further group of progressive retinal diseases known as the confirmation that the mutant PDEI) gene was responsible retinal pigment epithelial dystrophies. In at least some of for rd was provided by introducing a normal copy of the the affected breeds there would appear to be an inherited gene into rd mice and showing that the resulting predisposition for the condition which is modified by an transgenic mice did not develop retinal degeneration.24 environmental factor.° Unlike PRA the primary lesion is The dog was the second animal species in which a in the retinal pigment epithelium and is associated with retinal dystrophy causing mutation of the PDEI) gene lipofuscin deposition? Cone dysplasia has also been was identified. A hereditary retinal degeneration had described in the dog, although it is very rare. A recent been recognised in the Irish setter breed of dog since the study of affected dogs showed an absence of cone outer 1930s and reached a very high incidence in show dogs segment beta 3-transducin immunoreactivity, making it a until a strict test-mating programme was introduced in candidate gene for the defect.8 Congenital stationary the 1940s and l%Os. This form of PRA is known as rod­ night blindness occurs in animals as well as humans. It is cone dysplasia type one (rcdl). Histopathological described in the Appaloosa horse9 although the genetic investigations showed that in rcdl the retina develops defect has not been identified. In man several forms of normally for the first 13 days of life after which CSNB are recognised and can result from mutations of photoreceptor differentiation becomes arrested?S the rod opsin,1O PDEI),l1 rhodopsin kinase,12 alpha-1 Biochemical analysis showed that coincidental with transducin13 and arrestinl4 genes. We wait to find out arrested photoreceptor development there is an whether the Appaloosa horse defect will prove to be a abnormal elevation in retinal cGMP levels. The levels of homologue of any of these defects. Retinal dystrophies cGMP continue to rise until they reach about ten times have also been studied in a number of other species norma126 and are associated with reduced cGMP ranging from Drosophila to chickens, in which several phosphodiesterase activity?6,27 Investigations using forms are recognised, and primates, for example the Northern and slot blot analysis showed that the message Guinea baboon which suffers from a cone-rod for PDEI) was abnormally low before the retina I dystrophy. S degenerated.25

567 Cloning and sequencing of the PDEI3 gene by two wsa responsible for the rds phenotype was provided by groups revealed the same mutation in red 1 Irish setters in construction of transgenic rds mice in which a normal the UK and USA.28,29 The mutation was a guanine-to­ peripherin/RDS gene was expressed and resulted in adenine transition at nucleotide 2420 altering codon 807 photoreceptor cell rescue.52 The semidominant nature of from encoding tryptophan to a stop codon. Linkage the rds mutations is thought to be due to haplotype studies confirmed that the mutation was the site of the insufficiency. Heterozygous affected animals have a redl mutation?O single functional copy of the gene that does not make Screening of families with autosomal recessive sufficient product to prevent a slow retinal degeneration. retinitis pigmentosa revealed several with PDEI3 The homozygous affected mice have a complete absence mutations that co-segregated with their disease of the protein and develop a much more severe status?1-35 The affected patients were all compound phenotype. heterozygotes for PDEI3 mutations. Following identification of peripherin/RDS, screening of the gene in human patients with retinal dystrophies has led to the identification of over 40 different mutations Other animal models with cGMP accumulation within the gene.53 It is interesting to note that these Alteration of cGMP levels is a feature of other retinal mutations result in a wide range of phenotypes. Some dystrophies in animals. The collie dog suffers from a phenotypes show more severe rod dysfunction, as is form of PRA very similar, but non-allelic, to redl,36 This typical of classical autosomal dominant retinitis is termed rod-cone dysplasia type two (red2). With red2 pigmentosa; others predominantly have cone disease there is a very early arrest of photoreceptor development with rods affected to a lesser extent (for example, with an almost complete failure of rod outer segment cone-rod dystrophies); and others result in macular morphogenesis,37 and photoreceptor cell bodies go on to dystrophies. degenerate rapidly. There is an earlier and slightly greater elevation of retinal cGMP in red2 compared with Benefits of animal models of retinal dystrophies redl?8 Molecular investigations have excluded a1 transducin39 as the red2 locus and have failed to find any Studies of animal models of human retinal dystrophies sequence differences in the coding region of the genes for offer many obvious benefits. Molecular investigations cGMP phosphodiesterase a, 13 and -y subunits.40-42 can yield new potential candidate genes for human The Labrador retriever in Scandinavia suffers from a disease or even lead to the identification of previously photoreceptor dystrophy. Biochemical studies have unrecognised retinal genes. Detailed histopathological, demonstrated slightly raised levels of cGMP at early molecular and electrophysiological studies impossible in stages of retinal differentiation, although unlike in red 1 , human patients can be undertaken in animal models and cGMP phosphodiesterase catalytic activity appeared contribute to the understanding of disease mechanisms norma1.43 in the retina. The animal homologues of human disease Abyssinian cats with an autosomal dominant early­ can be used for the investigation of drug treatment or onset form of PRA given the gene symbol Rdy are also gene therapy, with the aim of preventing or slowing reported to exhibit increased cGMP levels early in the down photoreceptor degeneration. Initial work in the disease process.44 mouse is attractive because of the relative cheapness, short generation interval and well-characterised genetics. However, the eye of the mouse is unlike the human eye PeripherinlRDS associated diseases in its physical size and rod-to-cone ratio. Larger animal The retinal degeneration slow (rds) mouse phenotype is models should prove useful as intermediate models the result of a mutation in the peripherin/RDS gene, The between mouse and human eyes. For example, therapy rds mouse was first reported by Van Nie et al.45 in 1978 to treat PDEI3 defects could initially be undertaken in the and suffers from a semi-dominant disease characterised rd mouse and promising therapies then refined by by photoreceptor dysplasia followed by degeneration. experiments using the redl dog before considering Mice heterozygous for the mutation (rds /+) develop human clinical trials. dysplastic photoreceptor outer segments, which then Animal models of retinal dystrophies are an very slowly degenerate. The homozygous (rdslrds) mice important resource that requires detailed study, have a more severe phenotype: they fail to produce any outer segments, and photoreceptor degeneration is Note added in proof apparent by 3 weeks of age. Identification of the rds gene was achieved using a Subsequent to the submission of this paper a PRA­ combination of subtractive and differential hybridisation causing mutation has been identified in the gene methods.46.47 The gene identified was the peripherin/ encoding the alpha subunit of cGMP phosphodiesterase RDS (or peripherin 2) gene which encodes a structural in the Cardigan Welsh corgi breed of dog (Petersen-Jones protein present in photoreceptor outer segments.48.49 The SM, Entz D, Sargan DR. Mutation linked to cGMP­ rds mutation is due to a 9.2 kb insertion of foreign DNA phosphodiesterase alpha gene causes generalized into exon two of the gene creating a null mutation.50,51 progressive retinal atrophy in the Cardigan Welsh corgi. Final confirmation that the peripherin/RDS mutation Invest Ophthal Vis Sci (Suppl) 1998;39:4081).

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