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Mouse Mutants As Models for Congenital Retinal Disorders

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Experimental Eye Research 81 (2005) 503–512 www.elsevier.com/locate/yexer Review Mouse mutants as models for congenital retinal disorders Claudia Dalke*, Jochen Graw GSF-National Research Center for Environment and Health, Institute of Developmental Genetics, D-85764 Neuherberg, Germany Received 1 February 2005; accepted in revised form 1 June 2005 Available online 18 July 2005 Abstract Animal models provide a valuable tool for investigating the genetic basis and the pathophysiology of human diseases, and to evaluate therapeutic treatments. To study congenital retinal disorders, mouse mutants have become the most important model organism. Here we review some mouse models, which are related to hereditary disorders (mostly congenital) including retinitis pigmentosa, Leber’s congenital amaurosis, macular disorders and optic atrophy. q 2005 Elsevier Ltd. All rights reserved. Keywords: animal model; retina; mouse; gene mutation; retinal degeneration 1. Introduction Although mouse models are a good tool to investigate retinal disorders, one should keep in mind that the mouse Mice suffering from hereditary eye defects (and in retina is somehow different from a human retina, particular from retinal degenerations) have been collected particularly with respect to the number and distribution of since decades (Keeler, 1924). They allow the study of the photoreceptor cells. The mouse as a nocturnal animal molecular and histological development of retinal degener- has a retina dominated by rods; in contrast, cones are small ations and to characterize the genetic basis underlying in size and represent only 3–5% of the photoreceptors. Mice retinal dysfunction and degeneration. The recent progress of do not form cone-rich areas like the human fovea. Instead of genomic approaches has added increasing numbers of such three cone pigments present in the human retina, mice models. express only two distinct pigments with absorption maxima In recent years systematic phenotype-driven approaches near 350 and 510 nm (Lyubarsky et al., 1999). have been developed to screen for mice harboring In this review we discuss important mouse mutants for chemically induced mutations, mainly by use of N-ethyl- retinal degenerations (for cross information on their mutated N-nitrosourea (ENU), which predominantly causes point genes and chromosomal localization see Table 1 and Fig. 1). mutations (Justice et al., 1999). Moreover, many transgenic Concerning the nomenclature of genes and mutations, we and knockout animal models were created to investigate the follow the mouse genetic nomenclature as outlined by the Jackson Laboratory (http://www.informatics.jax.org). role of specific genes on retinal function. Finally, the gene- trapping method was developed for the systematic generation of knockout mice (Skarnes et al., 2004). 1.1. Retinal disorders including degeneration of photoreceptor cells Abbreviations BBS, Bardet-Biedl syndrome; ENU, N-ethyl-N-nitro- 1.1.1. Models for retinitis pigmentosa (RP) sourea; ERG, electroretinogram; LCA, Leber’s congenital amaurosis; RP, One of the first mouse mutants described in the field of retinitis pigmentosa; RPE, retinal pigment epithelium; STGD, Stargardt’s vision research was the rodless mouse (r; Keeler, 1924), macular dystrophy. * Corresponding author. Dr Claudia Dalke, GSF-National Research which carries a nonsense mutation in the Pde6b gene coding Center for Environment and Health, Institute of Developmental Genetics, for the b-subunit of phosphodiesterase. The gene mutation Ingolstaedter Landstr. 1, D-85764 Neuherberg, Germany. was later discovered in the retinal degeneration mouse E-mail address: [email protected] (C. Dalke). (actual gene symbol Pde6brd1, formerly referred to as rd1 or 0014-4835/$ - see front matter q 2005 Elsevier Ltd. All rights reserved. rd; Pittler and Baehr, 1991). A viral insertion in intron 1 of rd1 doi:10.1016/j.exer.2005.06.004 the Pde6b allele (Bowes et al., 1993)codingfor 504 C. Dalke, J. Graw / Experimental Eye Research 81 (2005) 503–512 Table 1 Overview of mutations in the mouse, affecting the structure or function of the retina. For allelic series just a few examples are listed Gene Symbol Chr. Defect alleles Mutation Reference (cM) Crb1 1 (73.0) Crb1rd8 1 bp deletion causing a frame shift and Mehalow et al., 2003 crumbs homolog 1 (Drosophila) premature stop codon Crb1tm1Wij Knockout, insertion of a hygromycin resistance van de Pavert cassette the promoter region, exon 1 and part of et al., 2004 intron 1 Cnga3 1 cyto- Cnga3tm1Biel Knockout, the gene was disrupted by replace- Biel et al., 1999 cyclic nucleotide gated band B ment of exon 7 with a neomycin resistance channel alpha 3 cassette Vsx1 2 (83.9) Vsx1tm1Bhr Knockout, a neo cassette replacing the coding Ohtoshi et al., 2004 visual system homeobox 1 region for the entire homeodomain and CVC homolog (zebrafish) domain Vsx1tm1Mci Knockout, a genomic fragment, was replaced Chow et al., 2004 with a neomycin selection cassette inserted by homologous recombination Abca4 3 (61.8) Abca4tm1Ght Knockout, replacement of a 4 kb genomic Weng et al., 1999 ATP-binding cassette, fragment containing the promoter and first exon sub-family A (ABC1), member 4 with a neomycin cassette Rpe65 3 (87.6) Rpe65tm1Tmr Knockout, exons 1–3 of the gene were replaced Redmond et al., 1998 retinal pigment epithelium 65 with a PGK-neo cassette Rpe65rd12 (retinal Nonsense mutation, base substitution (C to T) in Pang et al., 2005 degeneration 12) codon 44 Pde6b 5 (57.0) Pde6brd1 (retinal Nonsense mutation, C-A transversion in codon Pittler and Baehr, rod phospodiesterase, beta degeneration 1) 347 (exon 7) 1991 subunit (r,rodless; rd, retinal degeneration) Pde6brd10 (retinal Missense mutation in exon 13 Chang et al., 2002 degeneration 10) Pde6b2J 2 Jackson Point mutation in exon 16 Pde6batrd2 atypical ENU induced Thaung et al., 2002 retinal degeneration 2 Mitf 6 (40.0) Mitfmi-sp microphthal- Insertion of an extra C residue in the poly- Steingrimsson microphthalmia-associated mia spotted pyrimidine tract located upstream of an 18 bp et al., 1994 transcription factor alternative exon Mitfmi-vit vitiligo G to A transition at bp 793 that leads to an Steingrimsson aspartate to asparagine substitution et al., 1994 MitfMi-wh micro- T to A transversion at bp 764, which leads to an Steingrimsson phthalmia white isoleucine to asparagine substitution et al., 1994 Rho 6 (51.5) Rhotm1Jlem Knockout, a PGK-neo cassette was inserted into Lem et al., 1999 rhodopsin the first coding exon Rhotm1Phm Knockout, a neomycin cassette under the Humphries et al., control of a polymerase II promoter was 1997 inserted at codon 135 in exon 2 Crx 7 (8.5) Crxtm1Clc Knockout, the homeodomain coding region Furukawa et al., 1999 cone-rod homeobox containing exon 3 and a portion of exon 4 was containing gene replaced by a neomycin selection cassette Tub 7 (51.4) Tubtub-rd5 G to T transversion resulting in a larger Noben-Trauth tubby candidate gene transcript et al., 1996 Tubtm1Rok Knockout, a neomycin cassette replaced 16 kb Stubdal et al., 2000 of sequence spanning exons 1–8 Cln8 8 (6.0) Cln8mnd(motor neur- A single nucleotide insertion (267-268C, codon Ranta et al., 1999 ceroid-lipofuscinosis, neuronal 8 on degeneration) 90) predicts a frameshift and a truncated protein nr nervous 8 (8.0) nr spontaneous De Jager et al., 1998 Bbs2 8 synte- Bbs2tm1Vcs Knockout, exons 5–13 were replaced with a neo Nishimura et al., 2004 Bardet-Biedl syndrome 2 nic homolog (human) Mfrp 9 (25.5) Mfrprd6 4 bp deletion in the splice donor sequence of Kameya et al., 2002 membrane-type frizzled-related intron 4 - skipping of exon 4 (no frame shift) protein Bbs4 9 (33.0) Bbs4Gt1Nk A gene trap vector was inserted into intron 1, Kulaga et al., 2004 Bardet-Biedl syndrome 4 causing aberrant splicing homolog (human) Bbs4tm1Vcs Exons 6–11 were replaced with a neo cassette Mykytyn et al., 2004 (continued on next page) C. Dalke, J. Graw / Experimental Eye Research 81 (2005) 503–512 505 Table 1 (continued) Gene Symbol Chr. Defect alleles Mutation Reference (cM) Nr2e3 9 (33.5) Nr2e3rd7 Deletion of 380 bp (exon 4 and 5) - frame shift Akhmedov et al., nuclear receptor subfamily 2, resulting in a premature stop codon 2000 group E, member 3 (PNR- photoreceptor-specific nuclear receptor) Cln6 9 (35.0) Cln6nclf(neuronal cer- 1 bp insertion of a cysteine, located within a run Wheeler et al., 2002; ceroid-lipofuscinosis, neuronal 6 oid lipofuscinosis) of cysteines in exon 4, producing a frameshift at Gao et al., 2002 amino acid 103, followed by a premature stop codon Elovl4 9 synte- Transgene, 5-bp deletion corresponding to the Karan et al., 2005 elongation of very long nic human mutation (delAACTT at 790–794) chain fatty acids (FEN1/Elo2, SUR4/Elo3, yeast)-like 4 Pde6g 11 (75.0) Pde6gtm1Goff Knockout, a neomycin selection cassette Tsang et al., 1996 phosphodiesterase 6G, replaced genomic sequences including the third cGMP-specific, rod, gamma exon Aipl1 aryl hydrocarbon receptor- 11 synte- Aipl1tm1Mad Knockout, a neo replaced exons 1 and 2 Dyer et al., 2004 interacting protein-like 1 nic Aipl1tm1Visu Knockout, exons 2–5 were replaced with a Ramamurthy et al., neomycin resistance gene 2004 Chx10 12 (38.0) Chx10or Truslove, 1962 C. elegans ceh-10 homeo domain containing homolog Chx10or-J Premature stop codon (Y176stop) Theiler et al., 1976 Agtpbp1 13 (37.5) Agtpbp1pcd Purkinje mutation is likely in a regulatory region of the Fernandez-Gonzalez ATP/GTP binding protein 1 (Pcd, cell degeneration gene et al., 2002 Purkinje cell degeneration; Nna1) Agtpbp1pcd-2J Pur- 7.8 kb insertion into intron 13 Fernandez-Gonzalez kinje cell degener- et al., 2002 ation-2 Jackson Agtpbp1pcd-3J Pur- deletion that creates splice junction between Fernandez-Gonzalez kinje cell degener- exons 5 and 9 that introduces a premature stop et al., 2002 ation-3 Jackson codon Nrl 14 (19.5) Nrltm1Asw Knockout, a PGK-neomycin resistance cassette Swain et al., 2001 neural retina leucine zipper gene replaced the entire coding region (exons 2 and 3) Rpgrip1 14 synte- Rpgrip1tm1Tili Knockout, the gene was disrupted by insertion Zhao et al., 2003 retinitis pigmentosa GTPase nic of a large cassette containing 3 duplicated exons regulator interacting protein and a neomycin resistance gene.
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  • VSX1 Mutational Analysis in a Series of Italian Patients Affected by Keratoconus: Detection of a Novel Mutation

    VSX1 Mutational Analysis in a Series of Italian Patients Affected by Keratoconus: Detection of a Novel Mutation

    VSX1 Mutational Analysis in a Series of Italian Patients Affected by Keratoconus: Detection of a Novel Mutation Luigi Bisceglia,1 Marilena Ciaschetti,2 Patrizia De Bonis,1 Pablo Alberto Perafan Campo,2 Costantina Pizzicoli,3 Costanza Scala,1 Michele Grifa,1 Pio Ciavarella,1 Nicola Delle Noci,3 Filippo Vaira,4 Claudio Macaluso,5 and Leopoldo Zelante1 PURPOSE. Keratoconus is a noninflammatory corneal disorder Most cases of keratoconus appear to be sporadic, but a that is clinically and genetically heterogeneous. Mutations in positive family history has been documented in 6% to 10% of the VSX1 (visual system homeobox 1) gene have been identi- patients.5 Both recessive and dominant patterns of inheritance fied for two distinct, inherited corneal dystrophies: posterior have been described.6–8 Autosomal dominant inheritance has polymorphous corneal dystrophy and keratoconus. To evalu- more frequently been reported in families, showing incom- ate the possible role of the VSX1 gene in a series of Italian plete penetrance and variable expressivity. Subtle videokerato- patients, 80 keratoconus-affected subjects were screened for graphic anomalies have been reported among relatives of pa- mutations. tients with keratoconus, allowing the detection of low- ETHODS expressivity forms of keratoconus, usually referred to as M . The diagnosis of keratoconus was made on the basis 9–11 of clinical examination and corneal topography. The whole subclinical or forme fruste keratoconus. Multifactorial in- heritance and a major gene model have also been pro- coding region and the exon–intron junctions of the VSX1 gene 12,13 were analyzed by direct sequencing. posed. In some cases nongenetic causes have been postu- lated, such as eye rubbing or rigid contact lens wear, which RESULTS.