Human Molecular Genetics, 2002, Vol. 11, No. 10 1169-1176
© 2002 Oxford University Press
Molecular genetics of Leber congenital amaurosis
Department of Human Genetics, University Medical Center Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands
Received March 1, 2002; Accepted March 4, 2002
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONCLINICAL DEFINITION OF LCALCA GENES AND THEIR...MUTATION SPECTRUM OF LCA...IMPLICATIONS FOR ROUTINE DNA...PROSPECTS FOR THERAPYREFERENCES |
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Leber congenital amaurosis (LCA) is the most common inherited cause of blindness in childhood and is characterised by a severe retinal dystrophy before the age of one year. Six genes have been identified that together account for approximately half of all LCA patients. These genes are expressed preferentially in the retina or the retinal pigment epithelium. Their putative functions are quite diverse and include retinal embryonic development (CRX), photoreceptor cell structure (CRB1), phototransduction (GUCY2D), protein trafficking (AIPL1, RPGRIP1), and vitamin A metabolism (RPE65). The molecular data for CRB1 and RPE65 support previous hypotheses that LCA can represent the severe end of a spectrum of retinal dystrophies. Given the diverse mechanisms underlying the disease, future therapies of LCA may need to be tailored to certain genetically defined subgroups. Based on experimental evidence in mice and dogs, patients with disturbed retinal metabolism of vitamin A through a mutation in the RPE65 gene will likely be the first candidates for future therapeutic trials.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONCLINICAL DEFINITION OF LCALCA GENES AND THEIR...MUTATION SPECTRUM OF LCA...IMPLICATIONS FOR ROUTINE DNA...PROSPECTS FOR THERAPYREFERENCES |
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Leber congenital amaurosis (LCA) is the earliest and most severe form of all inherited retinal dystrophies, characterised by blindness or severe visual impairment from birth. LCA accounts for at least 5% of all retinal dystrophies and is one of the main causes of blindness in children (1–3). LCA is generally inherited in an autosomal recessive manner although some autosomal dominant families have been described (4,5). Since 1996, six genes involved in LCA have been identified, that is, aryl hydrocarbon receptor-interacting protein-like 1 (AIPL1) (6), Crumbs homolog 1 (CRB1) (7,8), cone–rod homeobox (CRX) (9), guanylate cyclase 2D (GUCY2D, RETGC1) (10), RPE65 (11), and retinitis pigmentosa GTPase regulator-interacting protein 1 (RPGRIP1) (12). In addition, linkage studies have revealed LCA loci on 14q24 (LCA3) (13) and 6q11-q16 (LCA5) (14). Other genes that have been associated with early-onset retinal dystrophy, including LRAT, MERTK, PROML1, and TULP1, are not considered LCA genes since the associated phenotypes are typical of juvenile or early-onset retinitis pigmentosa (RP) rather than LCA (15–18).
In this review we summarise clinical, biochemical, and molecular findings in LCA. Furthermore, we discuss the possibilities for routine DNA diagnostics and prospects for therapy.
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CLINICAL DEFINITION OF LCA |
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TOPABSTRACTINTRODUCTIONCLINICAL DEFINITION OF LCALCA GENES AND THEIR...MUTATION SPECTRUM OF LCA...IMPLICATIONS FOR ROUTINE DNA...PROSPECTS FOR THERAPYREFERENCES |
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LCA defines a clinically heterogeneous group of congenitally blind patients. Thorough clinical evaluation should be performed to exclude more complex or systemic disorders such as Joubert syndrome (MIM 213300), Lhermitte–Duclos syndrome (MIM 158350), Senior–Loken syndrome (MIM 266900), infantile Refsum disease (MIM 266510), and Zellweger syndrome (MIM 214100). Uncomplicated LCA is diagnosed as bilateral congenital blindness, with a diminished or absent electroretinogram (ERG). Visual difficulties are usually noticed before the age of six months. Based on the definition by Foxman and colleagues (19), the ERG should be extinguished before the age of one year. Patients rarely achieve a visual acuity better than 20/400 and usually present with high hyperopia of greater than five diopters (4). Many LCA patients show nystagmus, photophobia, eye poking, and sluggish pupils.
LCA represents the severe end of a spectrum of inherited retinal dystrophies that are often difficult to discriminate. Juvenile and early-onset RP are distinguished from LCA by a later age of onset, the absence of a searching nystagmus, night blindness, and a relatively good central visual acuity (19).
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LCA GENES AND THEIR PROTEIN PRODUCTS |
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TOPABSTRACTINTRODUCTIONCLINICAL DEFINITION OF LCALCA GENES AND THEIR...MUTATION SPECTRUM OF LCA...IMPLICATIONS FOR ROUTINE DNA...PROSPECTS FOR THERAPYREFERENCES |
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All six genes implicated in LCA are expressed exclusively or predominantly in the eye. AIPL1 (6), CRB1 (20), CRX (21–23), GUCY2D (24), and RPGRIP1 (25,26) are expressed by the photoreceptor cells (Fig. 1). In addition, AIPL1 is expressed in the pineal gland (6), CRB1 in the inner nuclear layer, the iris and specific structures of the brain (20), CRX in the inner nuclear layer and pineal gland (21,27), and RPGRIP1 in the testis (26,28) and in very low levels in the brain, liver, heart, spleen, and kidney (25). RPE65 is expressed specifically and abundantly in the retinal pigment epithelium (RPE) (29) (Fig. 1).
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Although the exact roles in eye development and homeostasis are not yet known for all LCA-associated genes, it is clear that their protein products have very diverse functions. AIPL1 is similar to aryl hydrocarbon receptor-interacting protein (AIP), a member of the FK-506-binding protein family. It contains three tetratricopeptide repeats (TPR), a motif that is found in proteins with nuclear transport or protein chaperone activity, suggesting that AIPL1 may be involved in retinal protein folding or trafficking (6).
CRB1 is homologous to the Drosophila Crumbs protein (30,31). Drosophila Crumbs is essential for establishing and maintaining apico-basal polarity in embryonic epithelia derived from the ectoderm (32). In particular, Crumbs is required for the biogenesis of the zonula adherens (ZA), a belt-like structure encircling the apex of epithelial cells (33). Recent studies show that Crumbs also has a role in photoreceptor morphogenesis (34,35). Crumbs is required to maintain the integrity of the ZA in photoreceptor cells, and is a central regulator in the biogenesis of the rhabdomere stalk, a structure that is similar to the inner segment of vertebrate photoreceptors (35). In the absence of Crumbs, the rhabdomeres, which are comparable to the vertebrate outer segments, do not elongate (34). The role of CRB1 in vertebrate photoreceptors may be similar to that of Crumbs, since in the mouse eye, Crb1 is localised in the inner segments of rods and cones, in the vicinity of the ZA. Interestingly, mouse Crb1 is also associated with the plasma membrane of the cone outer segments (35) (Fig. 1).
CRX is a homeobox transcription factor that plays a crucial role in the differentiation and maintenance of photoreceptor cells (23). It acts synergistically with the eye-specific transcription factors neural leucine-zipper (NRL) and homeobox protein RX, in the transactivation of photoreceptor-specific genes (21–23,36,37). CRX is required for the elongation of the photoreceptor outer segments, and is essential for the phototransduction pathway in both rods and cones (38).
GUCY2D is essential for the recovery of the dark state after the excitation process of photoreceptor cells by light stimulation. Photoexcitation stimulates hydrolysis of cGMP and closure of the cGMP-gated cation channels. Subsequently, the intracellular free Ca2+ concentration decreases, stimulating the production of retinal guanylate cyclase. In the recovery process of the phototransduction cascade, the cGMP levels are restored by the conversion of GTP to cGMP, which is catalysed by guanylate cyclase (3). GUCY2D is a transmembrane protein that is situated in different retinal cell types, but most abundantly in the marginal region of cone outer segments and to a lesser degree in rod outer segments (39) (Fig. 1).
RPE65 has a crucial role in the metabolism of vitamin A in the visual cycle (40). Regeneration of the visual pigment is performed in the RPE, and requires the isomerisation of all-trans-retinol to 11-cis-retinol, followed by the oxidation to 11-cis-retinal. In the absence of RPE65, the isomerisation process is blocked, leading to an accumulation of all-trans-retinyl esters (40). RPE65 may be responsible for the intracellular distribution of retinyl esters in the RPE (41), but the exact role of RPE65 in the isomerisation reaction remains to be determined (42).
RPGRIP1 is an interactor of the retinitis pigmentosa GTPase regulator (RPGR), which is involved in X-linked RP3. RPGRIP1 contains two coiled-coil domains that are homologous to those found in proteins involved in vesicular trafficking (25,26,28). In one study, RPGRIP1 has been co-localised with RPGR in the rod outer segments (25); in another study RPGRIP1 localised at the connecting cilium, near the junction between inner and outer segments (26) (Fig. 1). Its presumed function is to anchor RPGR within the cilium. In its turn, RPGR may play a role in maintaining the polarised protein distribution across the connecting cilium by facilitating directional transport or restricting redistribution (43).
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MUTATION SPECTRUM OF LCA GENES |
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TOPABSTRACTINTRODUCTIONCLINICAL DEFINITION OF LCALCA GENES AND THEIR...MUTATION SPECTRUM OF LCA...IMPLICATIONS FOR ROUTINE DNA...PROSPECTS FOR THERAPYREFERENCES |
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Mutations in the six currently identified LCA genes are estimated to underlie approximately 50% of LCA cases (Table 1), although a comprehensive mutation analysis of all six genes in the same patient group has not been performed. The six LCA genes show a high degree of allelic heterogeneity with only a few mutations found recurrently (Fig. 2). With the exception of RPGRIP1, each of the LCA genes has also been implicated in other retinal dystrophies.
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AIPL1 was identified as a positional candidate gene for the LCA4 locus on 17p13.1, where it localises near the GUCY2D gene. Mutations were found in two families that had previously been linked to 17p13.1, and in three of 14 families that had not been tested for linkage to 17p (6). Mutation analysis of AIPL1 in 188 probands with LCA identified mutations in 11 (5.8%) families (44). Additionally, AIPL1 mutations were found responsible for LCA with keratoconus in four Pakistani families (45). In total 39 AIPL1 alleles have been identified in these LCA families, and 27 (69%) of them represent null (nonsense, frameshift, or severe splice site) mutations. A nonsense mutation in the TPRIII domain (W278X) constitutes more than half (21/39) of all AIPL1 alleles. It was found predominantly in consanguineous Pakistani families and may represent a founder mutation (6,44,45). Mutation analysis of AIPL1 in a large cohort of patients with a range of retinal disorders revealed that AIPL1 may cause autosomal dominant retinal degeneration. The probands of two small families, who were diagnosed with cone–rod dystrophy CRD and juvenile RP respectively, are heterozygous for a 12-bp in frame deletion in the AIPL1 hinge region. However, in both cases autosomal dominant inheritance is dubious. Functional analysis of the 12bp deletion, and mutation analysis of a larger cohort of families with autosomal dominant retinal degenerations should be performed to confirm that AIPL1 can cause autosomal dominant CRD (adCRD) and RP (44).
The CRB1 gene was initially identified on the basis of its involvement in RP type 12, a juvenile/early-onset form of RP with a typical preserved para-arteriolar RPE (PPRPE) (30). More recently, CRB1 mutations were also found in RP patients with Coats-like exudative vasculopathy (7), and in RP patients without PPRPE (46). CRB1 mutations were found in 21 (9%) of 190 probands and seven (13.5%) of 52 probands with LCA (7,8). Although some mutations were found in both LCA and RP patients, identical combinations of mutations were not observed in both patient groups. The most frequent allele is C948Y (11/41 LCA alleles), which affects a conserved cysteine residue in the 14th EGF-like domain (30). C948Y was found homozygously in three unrelated LCA patients, while in RP patients it was found compound heterozygously with other, presumably milder missense mutations, or with a splice-site mutation that does not necessarily render the splice site completely inactive (7). Combinations of clear-cut null mutations were observed in three LCA patients, confirming that LCA is the most severe phenotype that can be associated with mutations in the CRB1 gene (7). Two cases of RP have been described that may carry null mutations on both alleles; one RP12 patient carries a homozygous AluY insertion in exon 7 (30) and the other patient has a homozygous 10 bp deletion in exon 9 (46). Although the consequence of the homozygous AluY insertion is not clear, it is possible that is does not completely inactivate CRB1 function by use of a cryptic splice site. The homozygous 10 bp deletion was found in a Pakistani RP family without PPRPE (46). Clinical data were only given for one individual, who has an age of onset of six months, suggesting that the diagnosis may be LCA. Although functional analysis of missense mutations remains to be performed, it is tempting to speculate that the residual CRB1 activity correlates inversely with the phenotypic severity of the retinal degeneration.
Defects in the CRX gene were initially found to cause adCRD (5,9,47). Considered a candidate gene on the basis of its function, CRX was subsequently tested for mutations in LCA patients (5,48–51). There is only a single report of a family in which LCA is caused by a homozygous CRX mutation (48). This mutation, R90W, is located in the homeodomain and results in a CRX protein with reduced DNA-binding and transcriptional regulatory activity (48). The mutation decreases the interaction of CRX with NRL (37) and also impairs its nuclear transport (52). Silva and colleagues (50) reported the identification of a heterozygous CRX null mutation (24–25insG) in an isolated LCA patient and in her father who had normal visual function. This observation implicates the presence of a second mutation, either in CRX or in another gene. Moreover, it strongly suggests that haploinsufficiency of CRX does not cause LCA. A heterozygous CRX mutation resulting in a four amino acid deletion has been identified in a large family with autosomal dominant LCA (5). Three de novo CRX frameshift mutations occurred heterozygously in sporadic LCA patients (9,49,50). These mutations are predicted to leave the DNA binding domain intact but to eliminate the OTX tail, which is important for CRX-mediated transactivation (53). Another heterozygous CRX frameshift mutation was detected in a mother and son affected with LCA (51). Although CRX phenotypes are usually described as severe, a marked visual improvement from birth to age 11 years was noted in the affected son (51). Possible explanations for the apparent heterozygosity are the presence of an unidentified mutation on the other CRX allele, or an additional mutation in another gene (digenic inheritance). Alternatively, CRX mutations may cause LCA by a dominant negative effect.
GUCY2D was identified by positional candidate gene cloning at the LCA1 locus in 17p13.1 (10). Subsequently, mutations have been identified in a large number of LCA families. Many patients carry protein truncating mutations on both alleles, which are expected to result in the total abolition of the cyclase activity of GUCY2D (3,10,49,54–56). Functional analysis of LCA mutations in vitro showed that missense mutations in the catalytic domain result in complete inability to hydrolyse GTP to cGMP (57,58). In contrast, missense mutations in the extracellular domain, except one affecting the initiation codon, showed normal catalytic activity. Presumably, these mutations may result in misfolding of the mutant protein and subsequent degradation in the endoplasmic reticulum (58). Complete loss-of-function of GUCY2D in LCA hinders the restoration of the basal level of cGMP of cone and rod photoreceptor cells, leading to a situation equivalent to consistent light exposure during photoreceptor development (56). GUCY2D mutations have also been found to cause adCRD (59–63). All adCRD mutations occur in a three codon sequence (aa 837-839) in the dimerisation domain. Although it has been suggested that the disease may be caused by a dominant negative effect by hindering dimerisation of the normal counterpart (3), functional analyses argue for a gain-of-function effect through enhanced sensitivity for its activating protein GCAP1 and decreased sensitivity to suppression (64–66). Consequently, dark-adapted photoreceptors have higher than normal rates of cGMP synthesis, which may cause the cone and rod degeneration.
The specific and abundant expression of the RPE65 gene in the RPE rendered it a promising candidate gene for retinal dystrophies. Indeed, molecular genetic studies revealed RPE65 mutations in patients with LCA and early onset RP (11,49,67–71). Combinations of null alleles were found in patients with LCA or RP, suggesting that other factors determine the clinical severity. Correlations between LCA genotypes and the disease severity have been established for patients with GUCY2D and RPE65 mutations (68,69). Both patient groups show the typical LCA features early in the disease process, including a nonrecordable ERG. Patients with GUCY2D mutations showed severe photophobia, nonrecordable visual fields, low visual acuity and a stationary congenital blindness. However, patients with RPE65 mutations preferred bright light, had better visual acuity, and sometimes demonstrated transient visual improvement.
RPGRIP1 mutations were found in three (5.3%) of 57 probands and in eight (5.6%) of 142 probands with LCA (12,72). Additionally, RPGRIP1 mutations were identified in two families that were linked to the 14q11 region through a genome-wide screen for homozygosity (72). Two missense mutations and one in frame deletion in the RPGRIP1 gene have been identified in LCA patients (72). The remaining ten are protein truncating mutations, which probably completely abolish RPGRIP1 function (12,72). RPGRIP1 is the only LCA gene that has not been associated with disease phenotypes other than LCA. Since mutations in its interactor RPGR cause X-linked RP3, it is conceivable that mutations that result in residual RPGRIP1 activity may cause phenotypes less severe than LCA, such as RP or CRD.
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IMPLICATIONS FOR ROUTINE DNA DIAGNOSTICS |
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TOPABSTRACTINTRODUCTIONCLINICAL DEFINITION OF LCALCA GENES AND THEIR...MUTATION SPECTRUM OF LCA...IMPLICATIONS FOR ROUTINE DNA...PROSPECTS FOR THERAPYREFERENCES |
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Identification of the molecular defects underlying retinal degeneration will allow clinicians to establish more accurate diagnoses and prognoses for LCA patients (73). Establishing the correct diagnosis based on clinical observations can be difficult, as exemplified by a clinical study that re-evaluated the diagnosis of 75 patients previously diagnosed with LCA (74). Thirty patients had been misdiagnosed, and were ultimately diagnosed with syndromes containing serious systemic malformations (74). Establishing a molecular diagnosis of LCA may also predict the visual prognosis for the patient. Initial genotype–phenotype correlation studies in LCA have already shown that patients carrying RPE65 mutations have a better visual prognosis than patients carrying GUCY2D mutations. In addition, identification of the disease-causing mutations in LCA patients will allow genetic counselling in the family of the patient. In the future, establishing a molecular diagnosis may be important for selecting patients for gene-specific therapies.
The six genes that have been identified account for approximately half of all LCA cases. Single-strand conformation analysis (SSCA) of these genes requires analysis of nearly 100 amplicons (Table 1). Routine mutation analysis of LCA patient samples using SSCA in standard DNA diagnostic facilities is therefore neither efficient nor cost-effective. Novel techniques based on capillary-electrophoresis are less time-consuming and might reduce the costs considerably. Alternatively, microarray-based primer extension of known mutations could be used, as recently shown for 
360 ABCA4 gene variants (75). However, owing to the high allelic heterogeneity in the known LCA genes we estimate that microarray-based analysis of currently known mutations would identify both mutant alleles in no more than 10% of patients. Before this technique can be used efficiently, additional LCA genes should be identified, and a large-scale, international effort to determine the genotypes of large numbers of patients should be performed to identify a larger fraction of LCA alleles.
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PROSPECTS FOR THERAPY |
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TOPABSTRACTINTRODUCTIONCLINICAL DEFINITION OF LCALCA GENES AND THEIR...MUTATION SPECTRUM OF LCA...IMPLICATIONS FOR ROUTINE DNA...PROSPECTS FOR THERAPYREFERENCES |
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As our knowledge of the molecular bases of inherited retinal diseases increases, possibilities to develop effective treatments come in sight. Therapeutic strategies based on pharmacological intervention, cell transplantation, or gene delivery are being evaluated in animal models (76).
A strategy that may be applicable to a wide range of retinal disorders is the transplantation of photoreceptors or RPE cells (77,78). Another strategy, gene therapy using neurotrophic factors, has been demonstrated to prolong survival of photoreceptors in different animal models (79–81). A delay in photoreceptor cell death has also been achieved by intraocular delivery of genes involved in apoptosis (82), the final common pathway of retinal degenerations.
Therapeutic strategies aimed at the correction of specific genetic and biochemical defects include pharmacological interventions, such as channel blockers in retinal degeneration (rd/rd) mice with a phosphodiesterase deficiency (83). In addition, there are a number of studies that report the successful replacement of loss-of-function alleles employing gene therapy in a variety of mouse models for recessive retinal degenerations (84). A particularly interesting example is gene transfer of peripherin-2 into the eyes of retinal degeneration slow (rds/rds) mice, which resulted in the formation of photoreceptor discs and outer segments (85). Treatment of diseases caused by dominant negative mutations is inherently more complex and long-term rescue of photoreceptors has only been demonstrated in mutant rhodopsin transgenic rats, a model of adRP (86). This result was achieved through virus-mediated delivery of ribozymes, catalytic RNA molecules that can be designed and used to cleave specific mutant mRNAs.
Important progress towards gene-specific therapies of LCA has recently been reported in animal models with defects in the RPE65 gene. One of these studies was performed in Rpe65-/-knockout mice, a genetically engineered model of LCA. Rpe65-deficiency in these mice leads to accumulation of all-trans-retinyl esters in the RPE, undetectable levels of 11-cis-retinal and rhodopsin, rod and cone photoreceptor dysfunction, and slow retinal degeneration (40,87). Oral administration of 9-cis-retinal resulted in the synthesis of rhodopsin and improved ERG responses (41), thus demonstrating that mechanism-based pharmacological intervention has the potential to restore vision in LCA. The other study used a naturally occurring large animal model of LCA, the RPE65-/- dog. These animals suffer from early and severe visual impairment due to a homozygous 4 bp deletion in the RPE65 gene. Histopathology shows prominent RPE inclusions, slightly abnormal photoreceptor morphology and slowly progressive retinal degeneration. Therapy consisted of the injection of adeno-associated virus carrying wildtype RPE65 into the subretinal space. ERG analysis of treated eyes revealed restoration of both rod and cone function. More importantly, a behavioral test demonstrated that the dogs had gained useful vision (88). It is clear that further assessments of long-term safety and efficacy are required and, since treatment may need to be applied very early in life, ethical aspects will have to be considered. Nevertheless, these advances are very encouraging and indicate that LCA patients carrying defects in the RPE65 gene are likely candidates for future clinical trials.
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ACKNOWLEDGEMENTS |
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The authors thank Drs H.G. Brunner, R. Roepman, and S. IJzer for a critical reading of the manuscript. Work in the authors' laboratory is supported by the Foundation Fighting Blindness, Inc., USA, and the British Retinitis Pigmentosa Society.
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FOOTNOTES |
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* To whom correspondence should be addressed. Tel: +31 24 3613750; Fax: +31 24 3540488; Email: F.Cremers{at}antrg.azn.nl
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REFERENCES |
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TOPABSTRACTINTRODUCTIONCLINICAL DEFINITION OF LCALCA GENES AND THEIR...MUTATION SPECTRUM OF LCA...IMPLICATIONS FOR ROUTINE DNA...PROSPECTS FOR THERAPYREFERENCES |
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1 Schappert-Kimmijser, J., Henkes, H.E. and van den Bosch, J. (1959) Amaurosis congenita (Leber). Arch. Ophthalmol., 61, 211–218.
2 Kaplan, J., Bonneau, D., Frézal, J., Munnich, A. and Dufier, J.-L. (1990) Clinical and genetic heterogeneity in retinitis pigmentosa. Hum. Genet., 85, 635–642.[ISI][Medline]
3 Perrault, I., Rozet, J.-M., Gerber, S., Ghazi, I., Leowski, C., Ducroq, D., Souied, E., Dufier, J.-L., Munnich, A. and Kaplan, J. (1999) Leber congenital amaurosis. Mol. Genet. Metab., 68, 200–208.[ISI][Medline]
4 Heckenlively, J.R. (1988) Retinitis Pigmentosa. Lippincott, Philadelphia.
5 Sohocki, M.M., Sullivan, L.S., Mintz-Hittner, H.A., Birch, D., Heckenlively, J.R., Freund, C.L., McInnes, R.R. and Daiger, S.P. (1998) A range of clinical phenotypes associated with mutations in CRX, a photoreceptor transcription-factor gene. Am. J. Hum. Genet., 63, 1307–1315.[ISI][Medline]
6 Sohocki, M.M., Bowne, S.J., Sullivan, L.S., Blackshaw, S., Cepko, C.L., Payne, A.M., Bhattacharya, S.S., Khaliq, S., Mehdi, S.Q., Birch, D.G. et al. (2000) Mutations in a new photoreceptor-pineal gene on 17p cause Leber congenital amaurosis. Nat. Genet., 24, 79–83.[ISI][Medline]
7 den Hollander, A.I., Heckenlively, J.R., van den Born, L.I., de Kok, Y.J.M., van der Velde-Visser, S.D., Kellner, U., Jurklies, B., van Schooneveld, M.J., Blankenagel, A., Rohrschneider, K. et al. (2001) Leber congenital amaurosis and retinitis pigmentosa with Coats-like exudative vasculopathy are associated with mutations in the Crumbs homologue 1 (CRB1) gene. Am. J. Hum. Genet., 69, 198–203.[ISI][Medline]
8
Lotery, A.J., Jacobson, S.G., Fishman, G.A., Weleber, R.G., Fulton, A.B., Namperumalsamy, P., Heon, E., Levin, A.V., Grover, S., Rosenow, J.R. et al. (2001) Mutations in the CRB1 gene cause Leber congenital amaurosis. Arch. Ophthalmol., 119, 415–420.
9 Freund, C.L., Wang, Q.-L., Chen, S., Muskat, B.L., Wiles, C.D., Sheffield, V.C., Jacobson, S.G., McInnes, R.R., Zack, D.J. and Stone, E.M. (1998) De novo mutations in the CRX homeobox gene associated with Leber congenital amaurosis. Nat. Genet., 18, 311–312.[ISI][Medline]
10 Perrault, I., Rozet, J.M., Calvas, P., Gerber, S., Camuzat, A., Dollfus, H., Châtelin, S., Souied, E., Ghazi, I., Leowski, C. et al. (1996) Retinal-specific guanylate cyclase gene mutations in Leber's congenital amaurosis. Nat. Genet., 14, 461–464.[ISI][Medline]
11 Marlhens, F., Bareil, C., Griffoin, J.-M., Zrenner, E., Amalric, P., Eliaou, C., Liu, S.-Y., Harris, E., Redmond, T.M., Arnaud, B. et al. (1997) Mutations in RPE65 cause Leber's congenital amaurosis. Nat. Genet., 17, 139–141.[ISI][Medline]
12 Dryja, T.P., Adams, S.M., Grimsby, J.L., McGee, T.L., Hong, D.-H., Li, T., Andréasson, S. and Berson, E.L. (2001) Null RPGRIP1 alleles in patients with Leber congenital amaurosis. Am. J. Hum. Genet., 68, 1295–1298.[ISI][Medline]
13 Stockton, D.W., Lewis, R.A., Abboud, E.B., Al Rajhi, A., Jabak, M., Anderson, K.L. and Lupski, J.R. (1998) A novel locus for Leber congenital amaurosis on chromosome 14q24. Hum. Genet., 103, 328–333.[ISI][Medline]
14 Dharmaraj, S., Li, Y., Robitaille, J.M., Silva, E., Zhu, D., Mitchell, T.N., Maltby, L.P., Baffoe-Bonnie, A.B. and Maumenee, I.H. (2000) A novel locus for Leber congenital amaurosis maps to chromosome 6q. Am. J. Hum. Genet., 66, 319–326.[ISI][Medline]
15 Hagstrom, S.A., North, M.A., Nishina, P.M., Berson, E.L. and Dryja, T.P. (1998) Recessive mutations in the gene encoding the tubby-like protein TULP1 in patients with retinitis pigmentosa. Nat. Genet., 18, 174–176.[ISI][Medline]
16 Gal, A., Li, Y., Thompson, D.A., Weir, J., Orth, U., Jacobson, S.G., Apfelstedt-Sylla, E. and Vollrath, D. (2000) Mutations in MERTK, the human orthologue of the RCS rat retinal dystrophy gene, cause retinitis pigmentosa. Nat. Genet., 26, 270–271.[ISI][Medline]
17
Maw, M.A., Corbeil, D., Koch, J., Hellwig, A., Wilson-Wheeler, J.C., Bridges, R.J., Kumaramanickavel, G., John, S., Nancarrow, D., Roper, K. et al. (2000) A frameshift mutation in prominin (mouse)-like 1 causes human retinal degeneration. Hum. Mol. Genet., 9, 27–34.
18 Thompson, D.A., Li, Y., McHenry, C.L., Carlson, T.J., Ding, X., Sieving, P.A., Apfelstedt-Sylla, E. and Gal, A. (2001) Mutations in the gene encoding lecithin retinol acyltransferase are associated with early-onset severe retinal dystrophy. Nat. Genet., 28, 123–124.[ISI][Medline]
19 Foxman, S.G., Heckenlively, J.R., Bateman, J.B. and Wirtschafter, J.D. (1985) Classification of congenital and early onset retinitis pigmentosa. Arch. Ophthalmol., 103, 1502–1506.[Abstract]
20 den Hollander, A.I., Ghiani, M., de Kok, Y.J.M., Wijnholds, J., Ballabio, A., Cremers, F.P.M. and Broccoli, V. (2002) Isolation of Crb1, a mouse homologue of Drosophila crumbs, and analysis of its expression pattern in eye and brain. Mech. Dev., 110, 203–207.[ISI][Medline]
21 Chen, S., Wang, Q.L., Nie, Z., Sun, H., Lennon, G., Copeland, N.G., Gilbert, D.J., Jenkins, N.A. and Zack, D.J. (1997) Crx, a novel Otx-like paired-homeodomain protein, binds to and transactivates photoreceptor cell-specific genes. Neuron, 19, 1017–1030.
22 Freund, C.L., Bellingham, J., Furukawa, T., Looser, J., Herbrick, J., Scherer, S., Tsui, L.C., Jacobson, S., Duncan, A., Papaioannou, M. et al. (1997) Cone–rod dystrophy due to mutations in a novel photoreceptor-specific homeobox gene (CRX) required for maintenance of the mammalian photoreceptor. Cell, 91, 543–553.[ISI][Medline]
23 Furukawa, T., Morrow, E.M. and Cepko, C.L. (1997) Crx, a novel otx-like homeobox gene, shows photoreceptor-specific expression and regulates photoreceptor differentiation. Cell, 91, 531–541.[ISI][Medline]
24 Shyjan, A.W., de Sauvage, F.J., Gillett, N.A., Goeddel, D.V. and Lowe, D.G. (1992) Molecular cloning of a retina-specific membrane guanylyl cyclase. Neuron, 9, 727–737.[ISI][Medline]
25
Roepman, R., Bernoud-Hubac, N., Schick, D., Maugeri, A., Berger, W., Ropers, H.-H., Cremers, F.P.M. and Ferreira, P.A. (2000) The Retinitis Pigmentosa GTPase Regulator (RPGR) interacts with novel transport-like proteins in the outer segments of rod photoreceptors. Hum. Mol. Genet., 9, 2095–2105.
26
Hong, D.H., Yue, G., Adamian, M. and Li, T. (2001) Retinitis pigmentosa GTPase regulator (RPGR)-interacting protein is stably associated with the photoreceptor ciliary axoneme and anchors RPGR to the connecting cilium. J. Biol. Chem., 276, 12091–12099.
27
Bibb, L.C., Holt, J.K., Tarttelin, E.E., Hodges, M.D., Gregory-Evans, K., Rutherford, A., Lucas, R.J., Sowden, J.C. and Gregory-Evans, C.Y. (2001) Temporal and spatial expression patterns of the CRX transcription factor and its downstream targets. Critical differences during human and mouse eye development. Hum. Mol. Genet., 10, 1571–1579.
28
Boylan, J.P. and Wright, A.F. (2000) Identification of a novel protein interacting with RPGR. Hum. Mol. Genet., 9, 2085–2093.
29
Nicoletti, A., Wong, D.J., Kawase, K., Gibson, L.H., Yang-Feng, T.L., Richards, J.E. and Thompson, D.A. (1995) Molecular characterization of the human gene encoding an abundant 61 kDa protein specific to the retinal pigment epithelium. Hum. Mol. Genet., 4, 641–649.
30 den Hollander, A.I., ten Brink, J.B., de Kok, Y.J.M., van Soest, S., van den Born, L.I., van Driel, M.A., van de Pol, T.J.R., Payne, A.M., Bhattacharya, S.S., Kellner, U. et al. (1999) Mutations in a human homologue of Drosophila crumbs cause retinitis pigmentosa (RP12). Nat. Genet., 23, 217–221.[ISI][Medline]
31
den Hollander, A.I., Johnson, K., de Kok, Y.J.M., Klebes, A., Brunner, H.G., Knust, E. and Cremers, F.P.M. (2001) CRB1 has a cytoplasmic domain that is functionally conserved between human and Drosophila. Hum. Mol. Genet., 10, 2767–2773.
32 Tepass, U., Theres, C. and Knust, E. (1990) Crumbs encodes an EGF-like protein expressed on apical membranes of Drosophila epithelial cells and required for organization of epithelia. Cell, 61, 787–799.[ISI][Medline]
33 Klebes, A. and Knust, E. (2000) A conserved motif in Crumbs is required for E-cadherin localisation and zonula adherens formation in Drosophila. Curr. Biol., 10, 76–85.[ISI][Medline]
34 Izaddoost, S., Nam, S.-C., Bhat, M.A., Bellen, H.J. and Choi, K.-W. Drosophila Crumbs is a positional cue in photoreceptor adherens junctions and rhabdomeres. Nature, 416, 178–183.
35 Pellikka, M., Tanentzapf, G., Pinto, M., Smith, C., McGlade,CJ., Ready, D.F. and Tepass, U. Crumbs, the Drosophila homologue of human CRB1/RP12, is essential for photoreceptor morphogenesis. Nature, 416, 143–149.
36
Kimura, A., Singh, D., Wawrousek, E.F., Kikuchi, M., Nakamura, M. and Shinohara, T. (2000) Both PCE-1/RX and OTX/CRX interactions are necessary for photoreceptor-specific gene expression. J. Biol. Chem., 275, 1152–1160.
37
Mitton, K.P., Swain, P.K., Chen, S., Xu, S., Zack, D.J. and Swaroop, A. (2000) The leucine zipper of NRL interacts with the CRX homeodomain. A possible mechanism of transcriptional synergy in rhodopsin regulation. J. Biol. Chem., 275, 29794–29799.
38 Furukawa, T., Morrow, E.M., Li, T., Davis, F.C. and Cepko, C.L. (1999) Retinopathy and attenuated circadian entrainment in Crx-deficient mice. Nat. Genet., 23, 466–470.[ISI][Medline]
39 Liu, X., Seno, K., Nishizawa, Y., Hayashi, F., Yamazaki, A., Matsumoto, H., Wakabayashi, T. and Usukura, J. (1994) Ultrastructural localization of retinal guanylate cyclase in human and monkey retinas. Exp. Eye Res., 59, 761–768.[ISI][Medline]
40 Redmond, T.M., Yu, S., Lee, E., Bok, D., Hamasaki, D., Chen, N., Goletz, P., Ma, J.-X., Crouch, R.K. and Pfeifer, K. (1998) Rpe65 is necessary for production of 11-cis-vitamin A in the retinal visual cycle. Nat. Genet., 20, 344–351.[ISI][Medline]
41
Van Hooser, J.P., Aleman, T.S., He, Y.G., Cideciyan, A.V., Kuksa, V., Pittler, S.J., Stone, E.M., Jacobson, S.G. and Palczewski, K. (2000) Rapid restoration of visual pigment and function with oral retinoid in a mouse model of childhood blindness. Proc. Natl Acad. Sci. USA, 97, 8623–8628.
42 Saari, J.C. (2001) The sights along route 65. Nat. Genet., 29, 8–9.[ISI][Medline]
43
Hong, D.H., Pawlyk, B.S., Shang, J., Sandberg, M.A., Berson, E.L. and Li, T. (2000) A retinitis pigmentosa GTPase regulator (RPGR)-deficient mouse model for X-linked retinitis pigmentosa (RP3). Proc. Natl Acad. Sci. USA, 97, 3649–3654.
44 Sohocki, M.M., Perrault, I., Leroy, B.P., Payne, A.M., Dharmaraj, S., Bhattacharya, S.S., Kaplan, J., Maumenee, I.H., Koenekoop, R., Meire, F.M. et al. (2000) Prevalence of AIPL1 mutations in inherited retinal degenerative disease. Mol. Genet. Metab., 70, 142–150.[ISI][Medline]
45 Damji, K.F., Sohocki, M.M., Khan, R., Gupta, S.K., Rahim, M., Loyer, M., Hussein, N., Karim, N., Ladak, S.S., Jamal, A. et al. (2001) Leber's congenital amaurosis with anterior keratoconus in Pakistani families is caused by the Trp278X mutation in the AIPL1 gene on 17p. Can. J. Ophthalmol., 36, 252–259.[ISI][Medline]
46 Lotery, A.J., Malik, A., Shami, S.A., Sindhi, M., Chohan, B., Maqbool, C., Moore, P.A., Denton, M.J. and Stone, E.M. (2001) CRB1 mutations may result in retinitis pigmentosa without para- arteriolar RPE preservation. Ophthalmic Genet., 22, 163–169.[Medline]
47 Swain, P.K., Chen, S., Wang, Q.L., Affatigato, L.M., Coats, C.L., Brady, K.D., Fishman, G.A., Jacobson, S.G., Swaroop, A., Stone, E. et al. (1997) Mutations in the cone–rod homeobox gene are associated with the cone-rod dystrophy photoreceptor degeneration. Neuron, 19, 1329–1336.[ISI][Medline]
48
Swaroop, A., Wang, Q.-L., Wu, W., Cook, J., Coats, C., Xu, S., Chen, S., Zack, D.J. and Sieving, P.A. (1999) Leber congenital amaurosis caused by a homozygous mutation (R90W) in the homeodomain of the retinal transcription factor CRX: direct evidence for the involvement of CRX in the development of photoreceptor function. Hum. Mol. Genet., 8, 299–305.
49
Lotery, A.J., Namperumalsamy, P., Jacobson, S.G., Weleber, R.G., Fishman, G.A., Musarella, M.A., Hoyt, C.S., Héon, E., Levin, A., Jan, J. et al. (2000) Mutation analysis of 3 genes in patients with Leber congenital amaurosis. Arch. Ophthalmol., 118, 538–543.
50
Silva, E., Yang, J.M., Li, Y., Dharmaraj, S., Sundin, O.H. and Maumenee, I.H. (2000) A CRX null mutation is associated with both Leber congenital amaurosis and a normal ocular phenotype. Invest. Ophthalmol. Vis. Sci., 41, 2076–2079.
51 Koenekoop, R.K., Loyer, M., Dembinska, O. and Beneish, R. Visual improvement in Leber congenital amaurosis and the CRX genotype. Ophthalmic Genet., 23, 49–59.
52
Fei, Y. and Hughes, T.E. (2000) Nuclear trafficking of photoreceptor protein crx: the targeting sequence and pathologic implications. Invest. Ophthalmol. Vis. Sci., 41, 2849–2856.
53
Chau, K.Y., Chen, S., Zack, D.J. and Ono, S.J. (2000) Functional domains of the cone–rod homeobox (CRX) transcription factor. J. Biol. Chem., 275, 37264–37270.
54
El Shanti, H., Al Salem, M., El Najjar, M., Ajlouni, K., Beck, J., Sheffiled, V.C. and Stone, E.M. (1999) A nonsense mutation in the retinal specific guanylate cyclase gene is the cause of Leber congenital amaurosis in a large inbred kindred from Jordan. J. Med. Genet., 36, 862–865.
55 Dharmaraj, S.R., Silva, E.R., Pina, A.L., Li, Y.Y., Yang, J.M., Carter, C.R., Loyer, M.K., El Hilali, H.K., Traboulsi, E.K., Sundin, O.K. et al. (2000) Mutational analysis and clinical correlation in Leber congenital amaurosis. Ophthalmic Genet., 21, 135–150.[Medline]
56 Perrault, I., Rozet, J.M., Gerber, S., Ghazi, I., Ducroq, D., Souied, E., Leowski, C., Bonnemaison, M., Dufier, J.L., Munnich, A. et al. (2000) Spectrum of retGC1 mutations in Leber's congenital amaurosis. Eur. J. Hum. Genet., 8, 578–582.[ISI][Medline]
57 Duda, T., Venkataraman, V., Goraczniak, R., Lange, C., Koch, K.W. and Sharma, R.K. (1999) Functional consequences of a rod outer segment membrane guanylate cyclase (ROS-GC1) gene mutation linked with Leber's congenital amaurosis. Biochemistry, 38, 509–515.[Medline]
58
Rozet, J.M., Perrault, I., Gerber, S., Hanein, S., Barbet, F., Ducroq, D., Souied, E., Munnich, A. and Kaplan, J. (2001) Complete abolition of the retinal-specific guanylyl cyclase (retGC-1) catalytic ability consistently leads to Leber congenital amaurosis (LCA). Invest. Ophthalmol. Vis. Sci., 42, 1190–1192.
59
Kelsell, R.E., Gregory-Evans, K., Payne, A.M., Perrault, I., Kaplan, J., Yang, R.-B., Garbers, D.L., Bird, A.C., Moore, A.T. and Hunt, D.M. (1998) Mutations in the retinal guanylate cyclase (RETGC-1) gene in dominant cone–rod dystrophy. Hum. Mol. Genet., 7, 1179–1184.
60 Perrault, I., Rozet, J.M., Gerber, S., Kelsell, R.E., Souied, E., Cabot, A., Hunt, D.M., Munnich, A. and Kaplan, J. (1998) A retGC-1 mutation in autosomal dominant cone–rod dystrophy. Am. J. Hum. Genet., 63, 651–654.[ISI][Medline]
61 Gregory-Evans, K., Kelsell, R.E., Gregory-Evans, C.Y., Downes, S.M., Fitzke, F.W., Holder, G.E., Simunovic, M., Mollon, J.D., Taylor, R., Hunt, D.M. et al. (2000) Autosomal dominant cone–rod retinal dystrophy (CORD6) from heterozygous mutation of GUCY2D, which encodes retinal guanylate cyclase. Ophthalmology, 107, 55–61.[ISI][Medline]
62
Weigell-Weber, M., Fokstuen, S., Torok, B., Niemeyer, G., Schinzel, A. and Hergersberg, M. (2000) Codons 837 and 838 in the retinal guanylate cyclase gene on chromosome 17p: hot spots for mutations in autosomal dominant cone–rod dystrophy? Arch. Ophthalmol., 118, 300.
63
Downes, S.M., Holder, G.E., Fitzke, F.W., Payne, A.M., Warren, M.J., Bhattacharya, S.S. and Bird, A.C. (2001) Autosomal dominant cone and cone–rod dystrophy with mutations in the guanylate cyclase activator 1A gene-encoding guanylate cyclase activating protein-1. Arch. Ophthalmol., 119, 96–105.
64 Duda, T., Krishnan, A., Venkataraman, V., Lange, C., Koch, K.W. and Sharma, R.K. (1999) Mutations in the rod outer segment membrane guanylate cyclase in a cone–rod dystrophy cause defects in calcium signaling. Biochemistry, 38, 13912–13919.[Medline]
65
Tucker, C.L., Woodcock, S.C., Kelsell, R.E., Ramamurthy, V., Hunt, D.M. and Hurley, J.B. (1999) Biochemical analysis of a dimerization domain mutation in RetGC-1 associated with dominant cone–rod dystrophy. Proc. Natl Acad. Sci. USA., 96, 9039–9044.
66
Wilkie, S.E., Newbold, R.J., Deery, E., Walker, C.E., Stinton, I., Ramamurthy, V., Hurley, J.B., Bhattacharya, S.S., Warren, M.J. and Hunt, D.M. (2000) Functional characterization of missense mutations at codon 838 in retinal guanylate cyclase correlates with disease severity in patients with autosomal dominant cone–rod dystrophy. Hum. Mol. Genet., 9, 3065–3073.
67
Morimura, H., Fishman, G.A., Grover, S.A., Fulton, A.B., Berson, E.L. and Dryja, T.P. (1998) Mutations in the RPE65 gene in patients with autosomal recessive retinitis pigmentosa or Leber congenital amaurosis. Proc. Natl Acad. Sci. USA., 95, 3088–3093.
68 Perrault, I., Rozet, J.M., Ghazi, I., Leowski, C., Bonnemaison, M., Gerber, S., Ducroq, D., Cabot, A., Souied, E., Dufier, J.L. et al. (1999) Different functional outcome of RetGC1 and RPE65 gene mutations in Leber congenital amaurosis. Am. J. Hum. Genet., 64, 1225–1228.[ISI][Medline]
69 Dharmaraj, S., Silva, E., Pina, A.L., Li, Y.Y., Yang, J.-M., Carter, R.C., Loyer, M., El-Hilali, H., Traboulsi, E., Sundin, O. et al. (2000) Mutational analysis and clinical correlation in Leber congenital amaurosis. Ophthalmic Genet., 21, 135–150.
70
Thompson, D.A., Gyürüs, P., Fleischer, L.L., Bingham, E.L., McHenry, C.L., Apfelstedt-Sylla, E., Zrenner, E., Lorenz, B., Richards, J.E., Jacobson, S.G. et al. (2000) Genetics and phenotypes of RPE65 mutations in inherited retinal degeneration. Invest. Ophthalmol. Vis. Sci., 41, 4293–4299.
71 Simovich, M.J., Miller, B., Ezzeldin, H., Kirkland, B.T., McLeod, G., Fulmer, C., Nathans, J., Jacobson, S.G. and Pittler, S.J. (2001) Four novel mutations in the RPE65 gene in patients with Leber congenital amaurosis. Hum. Mutat., 18, 164.
72 Gerber, S., Perrault, I., Hanein, S., Barbet, F., Ducroq, D., Ghazi, I., Martin-Coignard, D., Leowski, C., Homfray, T., Dufier, J.L. et al. (2001) Complete exon-intron structure of the RPGR-interacting protein (RPGRIP1) gene allows the identification of mutations underlying Leber congenital amaurosis. Eur. J. Hum. Genet., 9, 561–571.[ISI][Medline]
73
Gamm, D.M. and Thliveris, A.T. (2001) Implications of genetic analysis in Leber congenital amaurosis. Arch. Ophthalmol., 119, 426–427.
74 Lambert, S.R., Kriss, A., Taylor, D., Coffey, R. and Pembrey, M. (1989) Follow-up and diagnostic reappraisal of 75 patients with Leber's congenital amaurosis. Am. J. Ophthalmol., 107, 624–631.[ISI][Medline]
75 Allikmets, R., Hutchinson, A., Jaakson, K., Kuelm, M. and Pavel, H. (2001) Genotyping microarray (gene chip) for the ABCR (ABCA4) gene. Invest. Ophthalmol. Vis. Sci., 42(Suppl), S714.
76 Bessant, D.A.R., Ali, R.R. and Bhattacharya, S.S. (2001) Molecular genetics and prospects for therapy of the inherited retinal dystrophies. Curr. Opin. Genet. Dev., 11, 307–316.[ISI][Medline]
77 Sauve, Y., Klassen, H., Whiteley, S.J. and Lund, R.D. (1998) Visual field loss in RCS rats and the effect of RPE cell transplantation. Exp. Neurol., 152, 243–250.[ISI][Medline]
78 Kwan, A.S., Wang, S. and Lund, R.D. (1999) Photoreceptor layer reconstruction in a rodent model of retinal degeneration. Exp. Neurol., 159, 21–33.[ISI][Medline]
79 Cayouette, M. and Gravel, C. (1997) Adenovirus-mediated gene transfer of ciliary neurotrophic factor can prevent photoreceptor degeneration in the retinal degeneration (rd) mouse. Hum. Gene Ther., 8, 423–430.[ISI][Medline]
80
Cayouette, M., Behn, D., Sendtner, M., Lachapelle, P. and Gravel, C. (1998) Intraocular gene transfer of ciliary neurotrophic factor prevents death and increases responsiveness of rod photoreceptors in the retinal degeneration slow mouse. J. Neurosci., 18, 9282–9293.
81
Akimoto, M., Miyatake, S., Kogishi, J., Hangai, M., Okazaki, K., Takahashi, J.C., Saiki, M., Iwaki, M. and Honda, Y. (1999) Adenovirally expressed basic fibroblast growth factor rescues photoreceptor cells in RCS rats. Invest. Ophthalmol. Vis. Sci., 40, 273–279.
82 Bennett, J., Zeng, Y., Bajwa, R., Klatt, L., Li, Y. and Maguire, A.M. (1998) Adenovirus-mediated delivery of rhodopsin-promoted bcl-2 results in a delay in photoreceptor cell death in the rd/rd mouse. Gene Ther., 5, 1156–1164.[ISI][Medline]
83 Frasson, M., Sahel, J.A., Fabre, M., Simonutti, M., Dreyfus, H. and Picaud, S. (1999) Retinitis pigmentosa: rod photoreceptor rescue by a calcium-channel blocker in the rd mouse. Nat. Med., 5, 1183–1187.[ISI][Medline]
84 Bennett, J. and Maguire, A.M. (2000) Gene therapy for ocular disease. Mol. Ther., 1, 501–505.[ISI][Medline]
85 Ali, R.R., Sarra, G.M., Stephens, C., Alwis, M.D., Bainbridge, J.W., Munro, P.M., Fauser, S., Reichel, M.B., Kinnon, C., Hunt, D.M. et al. (2000) Restoration of photoreceptor ultrastructure and function in retinal degeneration slow mice by gene therapy. Nat. Genet., 25, 306–310.[ISI][Medline]
86 Lewin, A.S., Drenser, K.A., Hauswirth, W.W., Nishikawa, S., Yasumura, D., Flannery, J.G. and LaVail, M.M. (1998) Ribozyme rescue of photoreceptor cells in a transgenic rat model of autosomal dominant retinitis pigmentosa. Nat. Med., 4, 967–971.[ISI][Medline]
87 Seeliger, M.W., Grimm, C., Stahlberg, F., Friedburg, C., Jaissle, G., Zrenner, E., Guo, H., Reme, C.E., Humphries, P., Hofmann, F. et al. (2001) New views on RPE65 deficiency: the rod system is the source of vision in a mouse model of Leber congenital amaurosis. Nat. Genet., 29, 70–74.[ISI][Medline]
88 Acland, G.M., Aguirre, G.D., Ray, J., Zhang, Q., Aleman, T.S., Cideciyan, A.V., Pearce-Kelling, S.E., Anand, V., Zeng, Y., Maguire, A.M. et al. (2001) Gene therapy restores vision in a canine model of childhood blindness. Nat. Genet., 28, 92–95.[ISI][Medline]
89 Gu, S., Thompson, D.A., Srikumari, C.R.S., Lorenz, B., Finckh, U., Nicoletti, A., Murthy, K.R., Rathmann, M., Kumaramanickavel, G., Denton, M.J. et al. (1997) Mutations in RPE65 cause autosomal recessive childhood-onset severe retinal dystrophy. Nat. Genet., 17, 194–197.[ISI][Medline]
90 Hamel, C.P., Tsilou, E., Harris, E., Pfeffer, B.A., Hooks, J.J., Detrick, B. and Redmond, T.M. (1993) A developmentally regulated microsomal protein specific for the pigment epithelium of the vertebrate retina. J. Neurosci. Res., 34, 414–425.[ISI][Medline]
91 Tsilou, E., Hamel, C.P., Yu, S. and Redmond, T.M. (1997) RPE65, the major retinal pigment epithelium microsomal membrane protein, associates with phospholipid liposomes. Arch. Biochem. Biophys., 346, 21–27.[ISI][Medline]
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