Seminars in Ophthalmology, 2013; 28(5–6): 397–405 ! Informa Healthcare USA, Inc. ISSN: 0882-0538 print / 1744-5205 online DOI: 10.3109/08820538.2013.825277

CRB1: One Gene, Many Phenotypes* Miriam Ehrenberg1,2, Eric A. Pierce2, Gerald F. Cox3, and Anne B. Fulton1 1

Department of Ophthalmology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA, 2ERG Service, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, USA, and 3Division of Genetics and Department of Pediatrics, Boston Children’s Hospital and Harvard Medical School, Boston, Massachusetts, USA, and Clinical Development, Genzyme, Cambridge, Massachusetts, USA

ABSTRACT Mutations in the CRB1 gene cause severe retinal degenerations, which may present as Leber congenital amaurosis, early onset retinal dystrophy, retinitis pigmentosa, or cone-rod dystrophy. Some clinical features should alert the ophthalmologist to the possibility of CRB1 disease. These features are nummular pigmentation of the retina, atrophic macula, retinal degeneration associated with Coats disease, and a unique form of retinitis pigmentosa named para-arteriolar preservation of the retinal pigment epithelium (PPRPE). Retinal degenerations associated with nanophthalmos and hyperopia, or with keratoconus, can serve as further clinical cues to mutations in CRB1. Despite this, no clear genotype-phenotype relationship has been established in CRB1 disease. In CRB1-disease, as in other inherited retinal degenerations (IRDs), it is essential to diagnose the specific disease-causing gene for the disease as genetic therapy has progressed considerably in the last few years and might be applicable. Keywords: Coats disease, early onset rod-cone dystrophy (EORCD), inherited retinal dystrophy (IRD), Leber congenital amaurosis (LCA), preserved para-arteriolar retinal pigment epithelium (PPRPE), retinitis pigmentosa (RP)

INTRODUCTION

demonstrated a relationship. We discuss the importance of gene identification as a foundation for novel genetic treatments. In this paper, we follow the convention of italicized capital letters for human genes (i.e., CRB1) and lowercase letters for non-human genes (i.e., drosophila or zebrafish – crb).

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Mutations in almost 200 genes are known to cause inherited retinal degenerations (IRDs).1 IRDs comprise a heterogeneous group of diseases resulting from the death of photoreceptors (Figure 1A), and are characterized by progressive deterioration of retinal function with associated vision loss. Among the many IRD genes is crumbs homolog 1 (CRB1). Mutations in this single gene, CRB1, cause multiple ophthalmic phenotypes, including Leber congenital amaurosis (LCA), early onset rod-cone dystrophy (EORCD), retinitis pigmentosa (RP), and cone-rod dystrophy (CRD). In this paper, we summarize these phenotypes and highlight the features that may help the clinician identify CRB1 disease. We review the analyses of genotype and phenotype which have not

CRB1 GENE, PROTEIN, AND CELLULAR FUNCTION

The CRB1 gene is one of the human homologues of the crumbs (crb) gene in Drosophila. The gene is named for its function in the fly. If a homozygous loss-of-function mutation occurs in a crb gene of the Drosophila embryo, there is a failure in cuticle

*The authors thank Eliot Berson, MD, Berman-Gund Laboratory, Massachusetts Eye and Ear Infirmary, for his helpful critique of an earlier version of this paper. Received 10 April 2013; accepted 11 July 2013; published online 19 September 2013 Correspondence: Miriam Ehrenberg, MD, Department of Ophthalmology, Boston Children’s Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA. E-mail: [email protected]

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FIGURE 1. (A) The retinal layers. Note the outer limiting membrane, which is formed by zonula adherns between photoreceptor and Muller cells. (B) The CRB1 protein is found at the subapical region of the photoreceptors, which is located just apical to the zonula adherens in the photoreceptors. The subapical region and the zonula adherens segregate the photoreceptors into apical and basolateral compartments, which are critical for cell function and survival. (C) Schematic diagram of CRB1 protein (1406 amino acids). The protein consists of three structural regions: a long extracellular component (1345 amino acids), which contains 19 EGF-like repeats, and three laminin AG-like domains; a short transmembrane component; and an intracellular component (37 amino acids). No binding partners for the extracellular domain have been identified so far; most of the disease-causing mutations are found in this part. The intracellular domain forms a complex with additional intracellular proteins such as MPP5, PATJ, and MUPP1 and is critical for apicobasal cell polarity. The protein is also important for the integrity of the outer-limiting membrane, the normal development of the photoreceptor’s structure, and for cell-cell interactions. 254x190mm (96 x 96 DPI).

development, resulting in only a few ‘‘crumbs’’ of cuticle.2 Crb has long been implicated in retinal development and function.3–12 In humans, CRB1 is located on the long arm of chromosome 1 (1q31.1). It encodes a 1406 amino acid transmembrane protein, which is located in the subapical region of the photoreceptors (Figure 1B), and includes a long extracellular component, as well as a transmembrane and a short intracellular component (Figure 1C).2 Almost all CRB1 mutations occur in the extracellular domain.12,13The intracellular domain forms complexes with intracellular proteins that result in the crumbs protein complex.2,14,15 Studies of the CRB1 gene in humans, drosophila, zebrafish, and other species indicate a critical role of its protein in retinal development, structure, and function.4,5,9,11,12,16

OPHTHALMIC PHENOTYPES OF CRB1 DISEASE The phenotypes LCA, EORCD, RP, and CRD are broad categories based on age at first symptom and clinical findings (Table 1).

Leber Congenital Amaurosis (LCA) Mutations in CRB1 cause LCA8, which is among the most frequent causes of LCA. The frequency of LCA8

varies considerably between populations in different geographic regions and ranges from about 17% in Spain to 0% in Southern India.17–26 LCA presents with subnormal visual behavior in an otherwise healthy infant. ERG responses are markedly attenuated. In LCA8, visual abilities vary widely. The majority of affected patients retain walk-around vision in their first decade,27 during which median visual acuity is approximately 1 logMAR (20/200).19 Visual acuity deteriorates with advancing age.19,28 Nystagmus is frequent but not universal.4,19,20 LCA in general has been frequently associated with hyperopia.19,29–33 In LCA8, it is reported that homozygosity for the specific mutation p.Gly1103Arg (c.3307 G4A) in exon 9 is associated with significant hyperopia (þ5.00D to þ9.50D range) that increases with age.32 Keratoconus is a possible factor contributing to visual impairment in patients with LCA8, especially with increasing age.34–36 Keratoconus was attributed traditionally to eye rubbing,36 but recent work links the corneal shape abnormality to the CRB1 mutation itself.37 Beyer et al. reported a zebrafish model with a crb mutation that expresses severe corneal defects. Although human corneas express CRB1, the changes in the human cornea are less pronounced than in zebrafish.38 The frequency of keratoconus ranges from 14%29 to 70%35 in CRB1- disease. Although LCA8 patients may have a particular susceptibility to Seminars in Ophthalmology

CRB1: One Gene, Many Phenotypes 399 TABLE 1. Ophthalmic phenotypes for CRB1 disease. Category/Age at first symptom LCA/birth or early infancy

Typical ophthalmic findings

Other ophthalmic signs

CRB1 mutation frequency

Nummular pigmentation Widespread subretinal 0%–17% white dots, bone spicMacular atrophy ules, keratoconus, Thickened retina in OCT hyperopia, nyctalopia, nystagmus

Reference Sundaresan et al., Zernant et al., Henderson, Hanein et al., Li et al., Yzer et al., Vallespin et al., Coppieters et al., Corton et al., Beryozkin et al., Lotery et al., Jacobson et al.17–26,29,40

EORCD/childhood Widespread pigment clumping Preserved paraarteriolar RPE (PPRPE)

Keratoconus, hyperopia, EORCD-7% Corton et al., Henderson et al.19,44 nyctalopia, nystagmus Optic nerve drusen, vas- PPRPE- 66%-74% Corton et al., Den Hollander cular sheathing et al.13,44,73

RP/adolescence

Bone spicules, keratoconus, hyperopia, nyctalopia

Classic AR-RP Paravenous pigmented chorioretinal atrophy (PPCRA) Nanophthalmos optic nerve drusen Coats disease

0–6.5%

Corton et al., Den Hollander et al.13,44 McKay et al., Choi et al.51,52 Zenteno et al., Paun et al.53,54

Coats disease 31%–53%

Corton et al., Den Hollander et al., Bansal et al.13,44,45,47

LCA- Leber congenital amaurosis, EORCD- early onset Rod-Cone dystrophy, RP- retinitis pigmentosa, AR-RP- autosomal recessive retinitis pigmentosa.

keratoconus, it is by no means specific to CRB1 disease, as keratoconus has been reported in other causes of LCA, including AIPL1 (LCA4),27,35 GUCY2D (LCA1),27 and CRX (LCA7).37 The retinal hallmark of LCA8 is nummular pigment clumps, which are found in more than half of the patients (Figure 2).19,22,29,35,39 Although the nummular pigment patches are typical of CRB- disease, it is not pathognomonic and has also been described in retinal degenerations due to NR2E3, NRL, and TULP1 mutations.4 Also described in LCA8 patients are yellow-white retinal dots29,30 and salt-and-pepper retinal pigmentation. Other common retinal findings are macular atrophy, which is reported in 46%19 to 88%35 of individuals with a diagnosis of CRB1. Coloboma-like lesions in the macula have also been described,27 and have an estimated frequency of approximately 20%.29 Individuals with CRB1 mutations and macular colobomas have a variety of genotypes, and thus no clear genotype-phenotype correlation. Interestingly, Yzer et al.30 found evidence suggesting a correlation between a modifier allele (in AIPL1) and prominent atrophic macular lesions. Because of the atrophic changes in the macula, clinicians may include Stargardt disease in their differential diagnosis. Besides genotyping, ERG testing may help differentiate these two entities. Certain forms of LCA (e.g., LCA1 (GUC2YD) and LCA2 (RPE65)) have thin retinas secondary to the loss of the outer nuclear layer and photoreceptor outer and inner segments.40 In contrast to the thin retinas, Jacobson40 and Henderson et al.19 used OCT to demonstrate abnormally thick retinas (about 1.5 x more than normal) in some patients with CRB1 !

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FIGURE 2. A fundus photo from a patient with CRB1-related LCA demonstrating the typical nummular pigmentary changes and atrophic macula. 254x190mm (96 x 96 DPI).

disease. The OCT demonstrated a lack of distinct layering of the outer retina, a disorganization which resembles a stage of normal embryonal retinal development.40 The explanations that have been considered for this observation are either that this immature lamination pattern is due to the interruption of normal retinal development,40 or that this might be secondary to disruption of normal development of the photoreceptors and outer-limiting-membrane, as

400 M. Ehrenberg et al. CRB1 plays an important role in these processes.19 An interesting observation in a family with three affected individuals found that in the younger patients the retinal layers were well-delineated with preservation of the outer-limiting-membrane, but that the oldest subject had thickened lamination and loss of the outer-limiting-membrane layer.19 This observation implies a progressive process rather than an embryonic-developmental process. As pointed out by Henderson et al., longitudinal studies might help distinguish which of the two explanations is responsible for the abnormally thick retina.

Early Onset Rod Cone Dystrophy (EORCD) Some patients with CRB1-disease do not fall in the LCA category and do not fit the classic RP group either. Patients present after infancy with subnormal vision and night blindness. The median onset of symptoms is at 2.5 years. Visual acuities range from 0.16 logMAR to light perception. The majority of these patients present with hyperopia (range: þ0.50D to þ6.50D). Most cases reveal widespread pigment clumping at the level of the RPE.19 Preservation of the para-arteriolar retinal pigment epithelium (PPRPE) is a distinct form of EORCD. Patients present usually before the age of 10 years with the classic symptoms described above. Visual impairment is severe before age 20 years due to early involvement of the macular area. Fundus appearance in the early-to-middle stages of disease is unique and shows general RPE loss with preservation of the RPE adjacent to the arterioles, a pattern also detected by auto-fluorescence imaging.41 PPRPE may be associated with nystagmus, optic nerve–head drusen, vascular sheathing, and maculopathy.13,42,43 Fourteen29 to 18%19 of patients with CRB1-disease display PPRPE. When identifying a patient with PPRPE, the frequency of CRB1 mutations is high at roughly 75%.

Retinitis Pigmentosa (RP) RP is a rod-cone dystrophy. Patients present with night blindness and midperipheral visual field scotomas in adolescence. The disease progresses slowly and ultimately leads to severe visual loss. Progression is slowed in adults supplemented with vitamin A.44 Rod-mediated, and to some extent also conemediated, ERG responses are attenuated, and show delays in b-wave implicit times.45 The range of autosomal recessive RP patients carrying a mutation in CRB1 is 0% to 6.5%; the average is 2.7%.4,46 Retinal telangiectasias with or without exudative detachment (Coats disease) have been associated with some cases of IRDs19,47,48 in both children and

adults.49 The frequency of Coats disease among patients with RP is 1.2%–3.6%.39,50 CRB1 mutations were reported in more than 30% of patients with RP and Coats disease.4,46 Given that some patients developed this complication only in one eye and that not all siblings carrying the same mutations develop Coats disease, CRB1 mutations should be considered an important risk factor for Coats disease but additional genetic and/or environmental factors probably contribute as well.47 Henderson proposed that Coats disease develops in CRB1-disease due to loss of normal function and structure of the zonulaadherens (Figure 1B). When a mutation in CRB1 occurs, the zonula adherens does not function properly; there is a breakdown of the normal blood-retinal barrier, which exposes the immune system to retinal antigens and consequently triggers Coats disease.19 Coats disease associated with IRDs has also been described in patients who carry mutations in different genes.51,52 A unique form of autosomal dominant RP is pigment paravenous chorioretinal atrophy (PPCRA), which has also been linked to a single heterozygous mutation in CRB1. McKay et al.53 report a family with seven members affected with PPCRA. The earliest clinical sign detectable was peripheral inferior paravenous pigmentation with chorioretinal atrophy, which later progressed centrally. Family members showed variable expression, with males exhibiting a more severe phenotype. These investigators found that the CRB1 mutation segregated with disease in this family in a dominant inheritance mode, although only one unaffected individual was included. These data are consistent with the conclusion that a dominantly acting mutation in CRB1 causes PPCRA, although dominant inheritance of CRB1 has not been confirmed in other families. This would be especially noteworthy given that other forms of CRB1-disease are autosomal recessive. Another unusual form of RP recently linked to CRB1 is the RP, nanophthalmos, and optic-disc drusen syndrome. Two case series have been published, each reporting two siblings with retinal degeneration, an abnormally thick retina, nanophthalmos, hyperopia, and optic-nerve head drusen.54,55 In both families, novel mutations in the CRB1 gene were found. The authors hypothesized that since crb in drosophila is required for the normal control of the size of several organs, including the eye, it may also influence human eye size.

Cone-Rod Dystrophy Mutations in CRB1 may also cause a form of disease consistent with cone-rod dystrophy.19 Patients present in adolescence with poor central vision as their first symptom and later develop night blindness and Seminars in Ophthalmology

CRB1: One Gene, Many Phenotypes 401 visual field loss. ERG in these cases demonstrates cone responses that are reduced more than rod responses.

GENOTYPE-PHENOTYPE CORRELATIONS A number of studies have tried to link specific types of mutations in CRB1 to certain forms of disease.4,19,22,31,39,47,56 A meta-analysis of more than 240 patients with CRB1-related disease and over 150 gene variants found that most known mutations occur in exon 7 and 9 (27% and 41%, respectively) and 66% are missense mutations.4 In 2001, Den Hollander et al.47 suggested a possible biological explanation for the phenotypic variability produced by mutations in one gene. Among patients with CRB1-related disease, patients with the earlyonset LCA8 phenotype would carry two null alleles, whereas patients with the later-onset RP phenotype do not.47 Null alleles are expected to encode a nonfunctional protein, and therefore to cause a severe form of disease such as LCA. Other types of mutations may result in residual protein function, and therefore would be expected to cause a milder form of disease, such as RP. Null alleles are, indeed, more frequent in LCA cohorts. However, at times the same homozygous allele (e.g., p.Cys948Tyr) is found not only in patients with LCA, but also in RP or early onset IRD.4 Thus additional modifying factors, contributed by the individual’s genetic background, related to other CRB1 sequence variants or other genes or environmental factors, may modulate the phenotype.2,4,7,9,14 Most studies conclude that no correlation can be established between the type of the mutation or its location in the CRB1 gene and the form of the disease or its severity. While identification of the exact mutation does not allow prediction of the phenotype, certain phenotypes are associated with particular genetic diagnoses. For instance, the phenotypes suggestive of CRB1 mutations are fundus findings of nummular pigmentation, atrophic macula, PPRPE and IRD associated with Coats-like disease. These phenotypes have high frequency of CRB1 mutations. Also, the combination of IRD with nanophthalmos, with or without optic nerve drusen, has been associated with only two genes, CRB1 being one of them; the other is MFRP. A finding of a thickened retina in OCT may serve as another clue. A flowchart based on clinical findings has been created to lead clinicians towards the most relevant candidate gene in their LCA patients.20 Following this flowchart, the constellation of LCA with night blindness, hyperopia, macular changes, and VA in the range of 1/10- 2/10 is likely to be due to a mutation in CRB1 or CRX, another gene associated with LCA.20 !

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Importance of Identifying the Causative Gene Molecular diagnosis for patients with IRDs is important for several reasons. Certain ocular complications are more frequent with specific genes. Knowing the causative gene and the related ocular complications may facilitate providing the patient with anticipatory guidance. For instance, when examining a patient with CRB1-disease, the clinician should keep in mind the following possible ocular complications or recommendations: (1) Coats disease: A thorough examination for early signs of telangiectasia should be kept in mind, as treatment of Coats disease in the earlier phases prevents disease progression and visual loss, whereas treatment in the later phases is only meant to preserve a painless eye.49 (2) Keratoconus: Although vision loss is primarily caused by retinal degeneration, screening for and treating corneal ectasia may be beneficial for improving visual acuity. (3) As daylight exposure may accelerate photoreceptor degeneration,5 some investigators recommend counseling patients with CRB1-disease to reduce the amount or intensity of light reaching their eyes through the use of sunglasses as well as brimmed hats. IRD may raise clinical suspicion for a syndrome such as Bardet Biedel syndrome (retinal dystrophy, obesity, intellectual disability, post-axial polydactyly, hypogenitalism, and renal abnormalities) or SeniorLoken syndrome (retinal dystrophy and nephronophthisis). Systemic complications that are part of the syndrome may be life-threatening (e.g., renal failure). Having a specific clinical and molecular genetic diagnosis will provide caretakers with the most accurate and relevant disease information and will help to guide clinicians to screen for, monitor, and treat the relevant systemic manifestations. There has been great progress in the field of gene augmentation therapy. Three centers worldwide have used slightly different techniques to inject a viral vector carrying the RPE65 gene into the subretinal space of LCA2 patients. All three centers showed encouraging results in terms of safety and efficacy.56–58 Following the early success of these initial proof-of-concept trials, clinical trials of gene therapy for four other genetic forms of IRD are currently in progress (www.clinicaltrials.gov identifiers NCT01461213, NCT01482195, NCT01367444, NCT01505062).59 Further, studies in animal models have reported successful gene therapy for multiple additional genetic types of IRD.60–73 Hopefully, more genetic forms of IRD will be treatable by gene therapy in the future. A molecular genetic diagnosis is mandatory for participation in gene therapy trials because of genetic heterogeneity (i.e., the same IRD

402 M. Ehrenberg et al. phenotype being caused by more than one gene); in the case of LCA, at least 17 different genes give rise to the same phenotype.74 For future gene therapies that seek to address the underlying gene defect, it will be imperative to match patients by genotype with the appropriate gene therapy for their specific cause of disease. Clinicians must have a molecular diagnosis in order to provide accurate genetic counseling to affected families about the risk of recurrence.29 For example, the recurrence risk for LCA varies depending on whether the disease-causing mutation(s) occurred de novo in the affected child (generally 51%) or was inherited in an autosomal dominant (50%), autosomal recessive (25%), or X-linked (50% of boys) manner. It is essential to phenotype and genotype individuals with IRDs to better understand the molecular basis and pathogenesis of these degenerations, which will allow more therapies to develop.

SUMMARY In this paper, we reviewed the CRB1-associated oculopathies and included an overview of the genotype and phenotype analyses. The exact mechanism by which phenotypic variety derives from mutations in one gene is not clear and most investigators agree that additional genetic and/or environmental factors affect the expression of disease, and that these remain to be found. We emphasize the importance of securing a genetic diagnosis for patients with IRDs, as this will allow the clinician to tailor a specific treatment and follow-up plan and allow the patient to enroll in appropriate gene therapy trials (or receive appropriate gene therapy in the future). Moreover, collecting additional data will enlarge scientists’ and clinicians’ body of knowledge for the benefit of patients, currently and in the future.

DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

REFERENCES 1. Daiger SP, Sullivan LS, Bowne SJ, Rossiter BJ. RetNet Retinal Information Network. Available at: https:// sph.uth.edu/retnet/home.htm. Accessed March 8, 2013. 2. Gosens I, Den Hollander AI, Cremers FPM, Roepman R. Composition and function of the Crumbs protein complex in the mammalian retina. Experimental Eye Research 2008; 86(5):713–726. Available at: http://www.ncbi.nlm.nih. gov/pubmed/18407265. Accessed December 20, 2012.

3. Den Hollander I, Johnson K, De Kok YJ, et al. CRB1 has a cytoplasmic domain that is functionally conserved between human and Drosophila. Human Molecular Genetics 2001;10(24):2767–2773. Available at: http:// www.ncbi.nlm.nih.gov/pubmed/11734541. 4. Bujakowska K, Audo I, Mohand-Saı¨d S, et al. CRB1 mutations in inherited retinal dystrophies. Human Mutation 2012;33(2):306–315. Available at: http:// www.ncbi.nlm.nih.gov/pubmed/22065545. Accessed November 10, 2012. 5. Johnson K, Grawe F, Grzeschik N, Knust E. Drosophila crumbs is required to inhibit light-induced photoreceptor degeneration. Current Biology: CB 2002;12(19):1675–1680. Available at: http://www.ncbi.nlm.nih.gov/pubmed/ 12361571. 6. Fan S, Hurd TW, Liu C, et al. Polarity proteins control ciliogenesis via kinesin motor. Current Biology 2004;14: 1451–1461. 7. Van de Pavert SA, Kantardzhieva A, Malysheva A, et al. Crumbs homologue 1 is required for maintenance of photoreceptor cell polarization and adhesion during light exposure. Journal of Cell Science 2004;117(Pt 18):4169–4177. Available at: http://www.ncbi.nlm.nih.gov/pubmed/ 15316081. Accessed December 21, 2012. 8. Me´dina E, Lemmers C, Lane-Guermonprez L, Le Bivic A. Role of the crumbs complex in the regulation of junction formation in Drosophila and mammalian epithelial cells. Biology of the Cell under the auspices of the European Cell Biology Organization 2002;94(6):305–313. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12500938. 9. Mehalow AK, Kameya S, Smith RS, et al. CRB1 is essential for external limiting membrane integrity and photoreceptor morphogenesis in the mammalian retina. Human Molecular Genetics 2003;12(17):2179–2189. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12915475. Accessed January 14, 2013. 10. Richard M, Muschalik N, Grawe F, et al. A role for the extracellular domain of crumbs in morphogenesis of Drosophila photoreceptor cells. European Journal of Cell Biology 2009;88(12):765–777. Available at: http:// www.ncbi.nlm.nih.gov/pubmed/19717208. Accessed January 10, 2013. 11. Richard M, Roepman R, Aartsen WM, et al. Towards understanding CRUMBS function in retinal dystrophies. Human Molecular Genetics 2006;15 Spec No(2):R235–R243. Available at: http://www.ncbi.nlm.nih.gov/pubmed/ 16987889. Accessed December 21, 2012. 12. Chartier FJ-M, Hardy E´J-L, Laprise P. Crumbs limits oxidase-dependent signaling to maintain epithelial integrity and prevent photoreceptor cell death. The Journal of Cell Biology 2012;198(6):991–998. Available at: http:// www.ncbi.nlm.nih.gov/pubmed/22965909. Accessed December 21, 2012. 13. Den Hollander AI, Davis J, Van der Velde-Visser SD, et al. CRB1 mutation spectrum in inherited retinal dystrophies. Human Mutation 2004;24(5):355–369. Available at: http://www.ncbi.nlm.nih.gov/pubmed/ 15459956. Accessed January 9, 2013. 14. Bulgakova NA, Knust E. The Crumbs complex: From epithelial-cell polarity to retinal degeneration. Journal of Cell Science 2009;122(Pt 15):2587–2596. Available at: http:// www.ncbi.nlm.nih.gov/pubmed/19625503. Accessed December 3, 2012. 15. Kantardzhieva A, Gosens I, Alexeeva S, et al. MPP5 recruits MPP4 to the CRB1 complex in photoreceptors. Investigative Ophthalmology & Visual Science 2005; 46(6):2192–2201. Available at: http://www.ncbi.nlm.nih. gov/pubmed/15914641. Accessed December 21, 2012. Seminars in Ophthalmology

CRB1: One Gene, Many Phenotypes 403 16. Den Hollander AI, Ten Brink JB, De Kok YJ, et al. Mutations in a human homologue of Drosophila crumbs cause retinitis pigmentosa (RP12). Nature Genetics 1999; 23(2):217–221. Available at: http://www.ncbi.nlm.nih. gov/pubmed/10508521. 17. Sundaresan P, Vijayalakshmi P, Thompson S, et al. Mutations that are a common cause of Leber congenital amaurosis in northern America are rare in southern India. Molecular Vision 2009;15(May 2008):1781–1787. Available at: http://www.pubmedcentral.nih.gov/articlerender. fcgi?artid=2742639&tool=pmcentrez&rendertype=abstract. 18. Zernant J, Ku¨lm M, Dharmaraj S, et al. Genotyping microarray (disease chip) for Leber congenital amaurosis: Detection of modifier alleles. Investigative Ophthalmology & Visual Science 2005;46(9):3052–3059. Available at: http:// www.ncbi.nlm.nih.gov/pubmed/16123401. Accessed December 14, 2012. 19. Henderson RH, Mackay DS, Li Z, et al. Phenotypic variability in patients with retinal dystrophies due to mutations in CRB1. The British Journal of Ophthalmology 2011;95(6):811–817. Available at: http://www.ncbi.nlm. nih.gov/pubmed/20956273. Accessed December 21, 2012. 20. Hanein S, Perrault I, Gerber S, et al. Leber congenital amaurosis: Comprehensive survey of the genetic heterogeneity, refinement of the clinical definition, and genotypephenotype correlations as a strategy for molecular diagnosis. Human Mutation 2004;23(4):306–317. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15024725. Accessed December 21, 2012. 21. Li L, Xiao X, Li S, et al. Detection of variants in 15 genes in 87 unrelated Chinese patients with Leber congenital amaurosis. PloS One 2011;6(5):e19458. Available at: http://www.pubmedcentral.nih.gov/articlerender.fcgi? artid=3094346&tool=pmcentrez&rendertype=abstract. Accessed January 24, 2013. 22. Yzer S, Leroy BP, De Baere E, et al. Microarray-based mutation detection and phenotypic characterization of patients with Leber congenital amaurosis. Investigative Ophthalmology & Visual Science 2006;47(3):1167–1176. Available at: http://www.ncbi.nlm.nih.gov/pubmed/ 16505055. Accessed December 21, 2012. 23. Vallespin E, Cantalapiedra D, Riveiro-Alvarez R, et al. Mutation screening of 299 Spanish families with retinal dystrophies by Leber congenital amaurosis genotyping microarray. Investigative Ophthalmology & Visual Science 2007;48(12):5653–5661. Available at: http:// www.ncbi.nlm.nih.gov/pubmed/18055816. Accessed December 21, 2012. 24. Coppieters F, Casteels I, Meire F, et al. Genetic screening of LCA in Belgium: Predominance of CEP290 and identification of potential modifier alleles in AHI1 of CEP290-related phenotypes. Human Mutation 2010;31(10): E1709–E1766. Available at: http://www.pubmedcentral. nih.gov/articlerender.fcgi?artid=3048164&tool=pmcentrez& rendertype=abstract. Accessed December 21, 2012. 25. Corton M, Tatu SD, Avila-Fernandez A, et al. High frequency of CRB1 mutations as cause of Early-Onset Retinal Dystrophies in the Spanish population. Orphanet Journal of Rare Diseases 2013;8(1):20. Available at: http:// www.ncbi.nlm.nih.gov/pubmed/23379534. Accessed February 15, 2013. 26. Beryozkin A, Zelinger L, Bandah-Rozenfeld D, et al. Mutations in CRB1 are a relatively common cause of autosomal recessive early-onset retinal degeneration in the Israeli and Palestinian populations. Investigative Ophthalmology & Visual Science. 2013. Available at: http:// www.ncbi.nlm.nih.gov/pubmed/23449718. Accessed March 4, 2013. !

2013 Informa Healthcare USA, Inc.

27. Simonelli F, Ziviello C, Testa F, et al. Clinical and molecular genetics of Leber’s congenital amaurosis: A multicenter study of Italian patients. Investigative Ophthalmology & Visual Science 2007;48(9):4284–4290. Available at: http:// www.ncbi.nlm.nih.gov/pubmed/17724218. Accessed January 22, 2013. 28. Walia S, Fishman GA, Jacobson SG, et al. Visual acuity in patients with Leber’s congenital amaurosis and early childhood-onset retinitis pigmentosa. Ophthalmology 2010; 117(6):1190–1198. Available at: http://www.ncbi.nlm.nih. gov/pubmed/20079931. Accessed December 12, 2012. 29. Lotery AJ, Jacobson SG, Fishman GA, et al. Mutations in the CRB1 gene cause Leber congenital amaurosis. Archives of Ophthalmology 2001;119:415–420. 30. Yzer S, Fishman GA, Racine J, et al. CRB1 heterozygotes with regional retinal dysfunction: Implications for genetic testing of leber congenital amaurosis. Investigative Ophthalmology & Visual Science 2006;47(9):3736–3744. Available at: http://www.ncbi.nlm.nih.gov/pubmed/ 16936081. Accessed December 21, 2012. 31. Koenekoop RK. An overview of Leber congenital amaurosis: A model to understand human retinal development. Survey of Ophthalmology 2004;49(4):379–398. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15231395. Accessed November 19, 2012. 32. Abouzeid H, Li Y, Maumenee IH, et al. A G1103R mutation in CRB1 is co-inherited with high hyperopia and Leber congenital amaurosis. Ophthalmic genetics 2006;27(1):15–20. Available at: http://www.ncbi.nlm.nih.gov/pubmed/ 16543197. Accessed December 21, 2012. 33. Weleber RG. Infantile and childhood retinal blindnessœ: A molecular perspective (The Franceschetti Lecture). Ophthalmic Genetics 2002;23(2):71–97. 34. Heher KL, Traboulsi EI, Maumenee IH. The natural history of Leber’s congenital amaurosis. Age-related findings in 35 patients Ophthalmology 1992;99(2):241–245. Available at: http://www.ncbi.nlm.nih.gov/pubmed/1553215. Accessed January 17, 2013. 35. McKibbin M, Ali M, Mohamed MD, et al. Genotypephenotype correlation for Leber congenital amaurosis in Northern Pakistan. Archives of Ophthalmology 2010; 128(1):107–113. Available at: http://www.ncbi.nlm.nih. gov/pubmed/20065226. 36. Krachmer JH, Feder RS, Belin MW. Keratoconus and related noninflammatory corneal thinning disorders. Survey of Ophthalmology. 1984:293-322. Available at: http://www. sciencedirect.com.ezp-prod1.hul.harvard.edu/science/article/pii/0039625784900948#. Accessed January 22, 2013. 37. McMahon TT, Kim LS, Fishman GA, et al. CRB1 gene mutations are associated with keratoconus in patients with leber congenital amaurosis. Investigative Ophthalmology & Visual Science 2009;50(7):3185–3187. Available at: http:// www.ncbi.nlm.nih.gov/pubmed/19407021. Accessed December 21, 2012. 38. Beyer J, Zhao XC, Yee R, et al. The role of crumbs genes in the vertebrate cornea. Investigative Ophthalmology & Visual Science 2010;51(9):4549–4556. Available at: http://www. pubmedcentral.nih.gov/articlerender.fcgi?artid=2941173& tool=pmcentrez&rendertype=abstract. Accessed December 21, 2012. 39. Galvin JA, Fishman GA, Stone EM, Koenekoop RK. Evaluation of genotype-phenotype associations in leber congenital amaurosis. Retina (Philadelphia, Pa) 2005;25(7): 919–929. Available at: http://www.ncbi.nlm.nih.gov/ pubmed/16205573. 40. Jacobson SG, Cideciyan A V, Aleman TS, et al. Crumbs homolog 1 (CRB1) mutations result in a thick human retina with abnormal lamination. Human Molecular Genetics 2003;

404 M. Ehrenberg et al.

41.

42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

12(9):1073–1078. Available at: http://www.ncbi.nlm.nih. gov/pubmed/12700176. Accessed January 9, 2013. Tosi J, Tsui I, Lima L, et al. Autofluorescence imaging and phenotypic variance in a sibling pair with early onset retinal dystrophy due to defective CRB1 function. Current Eye Research 2009;34(5):395–400. Heckenlively JR. Preserved para-arteriole retinal pigment epithelium (PPRPE) in retinitis pigmentosa. The British Journal of Ophthalmology 1982;66(1):26–30. Available at: http://www.pubmedcentral.nih.gov/articlerender.fcgi? artid=1039707&tool=pmcentrez&rendertype=abstract. Van den Born LI, Van Soest S, Van Schooneveld MJ, et al. Autosomal recessive retinitis pigmentosa with preserved para-arteriolar retinal pigment epithelium. American Journal of Ophthalmology 1994;118(4):430–439. Available at: http://www.ncbi.nlm.nih.gov/pubmed/7943119. Accessed January 17, 2013. Berson EL. Long-term visual prognoses in patients with retinitis pigmentosa: the Ludwig von Sallmann lecture. Experimental Eye Research 2007;85(1):7–14. Available at: http://www.pubmedcentral.nih.gov/articlerender.fcgi? artid=2892386&tool=pmcentrez&rendertype=abstract. Accessed March 22, 2013. Berson EL. Electroretinographic findings in retinitis pigmentosa. Japanese Journal of Ophthalmology 1987; 31(3):327–348. Available at: http://www.ncbi.nlm.nih. gov/pubmed/2448510. Accessed April 9, 2013. Corton M, Tatu SD, Avila-Fernandez A, et al. High frequency of CRB1 mutations as cause of early-onset retinal dystrophies in the Spanish population. Orphanet Journal of Rare Diseases 2013;8(1):20. Available at: http:// www.ncbi.nlm.nih.gov/pubmed/23379534. Accessed February 15, 2013. Den Hollander a I, Heckenlively JR, Van den Born LI, et al. Leber congenital amaurosis and retinitis pigmentosa with Coats-like exudative vasculopathy are associated with mutations in the crumbs homologue 1 (CRB1) gene. American Journal of Human Genetics 2001;69(1):198–203. Available at: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1226034& tool=pmcentrez&rendertype=abstract. Spallone A, Carlevaro G, Ridling P. Autosomal dominant retinitis pigmentosa and Coats’-like disease. International Ophthalmology 1985;8(3):147–151. Available at: http:// www.ncbi.nlm.nih.gov/pubmed/4066158. Accessed January 17, 2013. Bansal S, Saha N, Woon WH. The management of ‘‘Coats’ response’’ in a patient with x-linked retinitis pigmentosa: A case report. ISRN Surgery 2011;2011:970361. Available at: http://www.pubmedcentral.nih.gov/articlerender. fcgi?artid=3200260&tool=pmcentrez&rendertype=abstract. Accessed January 17, 2013. Kan E, Yilmaz T, Aydemir O, et al. Coats-like retinitis pigmentosa: Reports of three cases. Clinical Ophthalmology (Auckland, NZ) 2007;1(2):193–198. Available at: http:// www.pubmedcentral.nih.gov/articlerender.fcgi?artid= 2704518&tool=pmcentrez&rendertype=abstract. Yzer S, Hollander AI Den, Lopez I, et al. Ocular and extra-ocular features of patients with Leber congenital amaurosis and mutations in CEP290. Molecular Vision 2012;18(February):412–425. Available at: http://www. pubmedcentral.nih.gov/articlerender.fcgi?artid=3283211& tool=pmcentrez&rendertype=abstract. Demirci FYK, Rigatti BW, Mah TS, Gorin MB. A novel RPGR exon ORF15 mutation in a family with X-linked retinitis pigmentosa and Coats’-like exudative vasculopathy. American Journal of Ophthalmology 2006;141(1):208–210. Available at: http://www.ncbi.nlm.nih.gov/pubmed/ 16387007. Accessed February 4, 2013.

53. McKay GJ, Clarke S, Davis JA, et al. Pigmented paravenous chorioretinal atrophy is associated with a mutation within the crumbs homolog 1 (CRB1) gene. Investigative Ophthalmology & Visual Science 2005;46(1):322–328. Available at: http://www.ncbi.nlm.nih.gov/pubmed/ 15623792. Accessed December 21, 2012. 54. Zenteno JC, Buentello-Volante B, Ayala-Ramirez R, Villanueva-Mendoza C. Homozygosity mapping identifies the Crumbs homologue 1 (Crb1) gene as responsible for a recessive syndrome of retinitis pigmentosa and nanophthalmos. American Journal of Medical Genetics Part A 2011;155A(5):1001–1006. Available at: http://www. ncbi.nlm.nih.gov/pubmed/21484995. Accessed December 13, 2012. 55. Paun CC, Pijl BJ, Siemiatkowska AM, et al. A novel crumbs homolog 1 mutation in a family with retinitis pigmentosa, nanophthalmos, and optic disc drusen. Molecular Vision 2012;18(October):2447–2453. Available at: http://www. pubmedcentral.nih.gov/articlerender.fcgi?artid=3472923& tool=pmcentrez&rendertype=abstract. 56. Chung DC, Traboulsi EI. Leber congenital amaurosis: Clinical correlations with genotypes, gene therapy trials update, and future directions. Journal of AAPOS: The Official Publication of the American Association for Pediatric Ophthalmology and Strabismus/American Association for Pediatric Ophthalmology and Strabismus 2009;13(6):587–592. Available at: http://www.ncbi.nlm.nih.gov/pubmed/ 20006823. Accessed December 21, 2012. 57. Maguire AM, Simonelli F, Pierce EA, et al. Safety and efficacy of gene transfer for Leber’s congenital amaurosis. The New England Journal of Medicine 2008;358(21): 2240–2248. Available at: http://www.pubmedcentral.nih. gov/articlerender.fcgi?artid=2829748&tool=pmcentrez& rendertype=abstract. Accessed November 1, 2012. 58. Bainbridge JWB, Smith AJ, Barker SS, et al. Effect of gene therapy on visual function in Leber’s congenital amaurosis. The New England Journal of Medicine 2008; 358(21):2231–2239. Available at: http://www.ncbi.nlm. nih.gov/pubmed/18441371. Accessed November 1, 2012. 59. Anon. ClinicalTrials.gov. Available at: http://www. clinicaltrials.gov/. Accessed March 8, 2013. 60. Ali RR, Sarra GM, Stephens C, et al. Restoration of photoreceptor ultrastructure and function in retinal degeneration slow mice by gene therapy. Nature Genetics 2000; 25(3):306–310. Available at: http://www.ncbi.nlm.nih. gov/pubmed/10888879. 61. Min SH, Molday LL, Seeliger MW, et al. Prolonged recovery of retinal structure/function after gene therapy in an Rs1h-deficient mouse model of x-linked juvenile retinoschisis. Molecular Therapy: The Journal of the American Society of Gene Therapy 2005;12(4):644–651. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16027044. Accessed March 7, 2013. 62. Alexander JJ, Umino Y, Everhart D, et al. Restoration of cone vision in a mouse model of achromatopsia. Nature Medicine 2007;13(6):685–687. Available at: http:// www.ncbi.nlm.nih.gov/pubmed/17515894. Accessed March 6, 2013. 63. Pang J-J, Boye SL, Kumar A, et al. AAV-mediated gene therapy for retinal degeneration in the rd10 mouse containing a recessive PDEbeta mutation. Investigative Ophthalmology & Visual Science 2008;49(10):4278–4283. Available at: http://www.ncbi.nlm.nih.gov/pubmed/ 18586879. Accessed March 7, 2013. 64. Tam LCS, Kiang A-S, Kennan A, et al. Therapeutic benefit derived from RNAi-mediated ablation of IMPDH1 transcripts in a murine model of autosomal dominant retinitis pigmentosa (RP10). Human Molecular Genetics 2008;17(14):2084–2100. Available at: http:// Seminars in Ophthalmology

CRB1: One Gene, Many Phenotypes 405

65.

66.

67.

68.

69.

!

www.ncbi.nlm.nih.gov/pubmed/18385099. Accessed March 7, 2013. Cai X, Conley SM, Nash Z, et al. Gene delivery to mitotic and postmitotic photoreceptors via compacted DNA nanoparticles results in improved phenotype in a mouse model of retinitis pigmentosa. FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology 2010;24(4):1178–1191. Available at: http://www.pubmedcentral.nih.gov/articlerender. fcgi?artid=2845431&tool=pmcentrez&rendertype=abstract. Accessed March 7, 2013. Sun X, Pawlyk B, Xu X, et al. Gene therapy with a promoter targeting both rods and cones rescues retinal degeneration caused by AIPL1 mutations. Gene Therapy 2010; 17(1):117–131. Available at: http://www.pubmedcentral. nih.gov/articlerender.fcgi?artid=2804971&tool=pmcentrez& rendertype=abstract. Accessed March 7, 2013. Pawlyk BS, Bulgakov O V, Liu X, et al. Replacement gene therapy with a human RPGRIP1 sequence slows photoreceptor degeneration in a murine model of Leber congenital amaurosis. Human Gene Therapy 2010; 21(8):993–1004. Available at: http://www.pubmedcentral. nih.gov/articlerender.fcgi?artid=2928706&tool=pmcentrez& rendertype=abstract. Accessed March 7, 2013. Simons DL, Boye SL, Hauswirth WW, Wu SM. Gene therapy prevents photoreceptor death and preserves retinal function in a Bardet-Biedl syndrome mouse model. Proc Natl Acad Sci USA 2011 Apr 12;108(15): 6276–6281. Mao H, James T, Schwein A, et al. AAV delivery of wild-type rhodopsin preserves retinal function in a mouse model of autosomal dominant retinitis pigmentosa.

2013 Informa Healthcare USA, Inc.

70.

71.

72.

73.

74.

Human Gene Therapy 2011;22(5):567–575. Available at: http://www.pubmedcentral.nih.gov/articlerender.fcgi? artid=3131806&tool=pmcentrez&rendertype=abstract. Accessed March 7, 2013. Mihelec M, Pearson RA, Robbie SJ, et al. Long-term preservation of cones and improvement in visual function following gene therapy in a mouse model of leber congenital amaurosis caused by guanylate cyclase-1 deficiency. Human Gene Therapy 2011;22(10): 1179–1190. Available at: http://www.pubmedcentral.nih. gov/articlerender.fcgi?artid=3205803&tool=pmcentrez& rendertype=abstract. Accessed March 7, 2013. Han Z, Conley SM, Makkia RS, et al. DNA nanoparticlemediated ABCA4 delivery rescues Stargardt dystrophy in mice. The Journal of Clinical Investigation 2012;122(9): 3221–3226. Beltran WA, Cideciyan A V, Lewin AS, et al. Gene therapy rescues photoreceptor blindness in dogs and paves the way for treating human X-linked retinitis pigmentosa. Proc Natl Acad Sci USA 2012 Feb 7;109(6): 2132–2137. Pang J, Deng W-T, Dai X, et al. AAV-mediated cone rescue in a naturally occurring mouse model of CNGA3-achromatopsia. PloS One 2012;7(4):e35250. Available at: http:// www.pubmedcentral.nih.gov/articlerender.fcgi?artid= 3324465&tool=pmcentrez&rendertype=abstract. Accessed March 7, 2013. Falk MJ, Zhang Q, Nakamaru-Ogiso E, et al. NMNAT1 mutations cause Leber congenital amaurosis. Nature Genetics 2012;44(9):1040–1045. Available at: http://www. ncbi.nlm.nih.gov/pubmed/22842227. Accessed November 5, 2012.

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