Molecular Vision 2000; 6:116-124 <http://www.molvis.org/molvis/v6/a16/>
Received 21 April 2000 | Accepted 23 June 2000 | Published 8 July 2000
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Review

A brief review of retinitis pigmentosa and the identified retinitis pigmentosa genes

James K. Phelan,1 Dean Bok2,3,4
 
 

1Department of Pediatrics, 2Department of Neurobiology, 3Brain Research Institute, and 4Jules Stein Eye Institute, School of Medicine, University of California Los Angeles, Los Angeles, CA

Correspondence to: Dr. Dean Bok, Rm. B-182, Jules Stein Eye Institute, 100 Stein Plaza, Los Angeles, CA, 90095; Phone: (310) 825-6737; FAX: (310) 794-2144; email: bok@jsei.ucla.edu


Abstract

The family of inherited ocular diseases that is collectively known as retinitis pigmentosa is a major cause of progressive retinal disease worldwide. As such, this family of diseases has been the object of much scientific scrutiny, both clinical and basic. The recent application of molecular genetic analyses has heralded the rapid elucidation of the underlying gene defects in many cases. In this article, the fundamental clinical and electroretinographic characteristics of retinitis pigmentosa will be recalled. Additionally, the current understanding of the genetic causes of retinitis pigmentosa will be reviewed, and the identified causative genes will be classified into groups related by function.


Introduction

Retinitis pigmentosa (RP) has been the name for over 140 years for a number of related dysfunctions of the retina with a combined incidence of approximately 1/3500 [1,2]. There are many forms of these diseases now described, and a variety of partial and complete synonyms for the term "retinitis pigmentosa" have been used in the literature [3]. The similarities that have led to the common grouping of these diseases are based on clinical symptoms, electroretinographic phenotype, and/or genetics. Simultaneously, several classification schemes have been proffered to distinguish the diseases based primarily on the variability of these three diagnostic indices. The current proliferation of genetic knowledge (summarized at RetNet), however, is generating rapid evolution of the systematic approaches to classification of RP diseases. In this article, the spectrum of RP diseases will briefly be reviewed in terms of the clinical, electroretinographic, and genetic characteristics, and the characterized causative genes will be divided according to function. Potential mechanisms of photoreceptor cell degeneration have been recently reviewed [3-5], and will not be treated in depth.

In addition to the typical forms of RP, there are a number of related, or allied, diseases. These may be similar by any of the three diagnostic criteria mentioned above. There are also syndromic forms of RP, in which the disease is present as a component of a multisystem disorder. Where relevant, relationships between RP and these allied diseases and syndromes will be noted. Recent reviews have summarized current research on a number of these diseases, including Leber congenital amaurosis [6], Stargardt disease and fundus flavimaculatus [7], macular degeneration [8], cone dystrophy [9], and the Refsum diseases [10].


Clinical Description

Historically, RP patients were believed to suffer from retinal inflammation in conjunction with observed retinal pigmentary changes [1]. Inflammation is no longer considered causal in RP, and cases of true RP are now viewed as genetic in origin. The pigmentary changes remain a common factor in RP diagnoses. Typically, these result from the release of pigment by degenerating cells in the retinal pigment epithelium (RPE). The pigment granules accumulate in perivascular clusters, known as "bone-spicule formations" due to their morphological appearance, in the neural retina. Consequently, early in the disease the pigmented posterior pole of the eye, the fundus, develops a mottled or granular appearance. This is followed by the development of bone-spicule pigmentary deposits overlying the depigmented fundus. Variability in the course of pigmentary changes can cause hypopigmentation, translucence, or window-like holes through the RPE, and rounded clumps of pigment to form in the neural retina [11].

In typical cases, known as rod-cone RP, the rods are the predominantly affected photoreceptor cells [1,11]. This generates a number of characteristic, clinical symptoms including night blindness at an early age or stage of the disease, and bilateral symmetric loss of the mid-peripheral visual fields. Although there is usually relative preservation of macular vision, the visual field defects gradually increase both centrally and peripherally. With progression, cone photoreceptor cells are also affected and day vision and central visual acuity are compromised. The rate of visual failure is variable, but total blindness is eventually possible. The final common pathway of photoreceptor cell death is apoptosis [4,12-14].

A common variant of RP shows the simultaneous involvement of cone photoreceptor cells [1,9,15,16]. These forms, referred to as cone-rod dystrophy or cone-rod degeneration, show a more central loss of the visual field and greater early changes to the cone dominated central retina. The visual symptoms, however, are pan-retinal and often include loss of night vision and peripheral visual fields. The allied diseases of cone dystrophy and macular degeneration are disorders of the central retina in which the cones are the predominantly affected photoreceptor cells. In these cases the central visual fields are lost, while night and peripheral vision are preserved.

The age of onset of RP can vary from infancy through late middle age [1,17]. The age at which symptoms become clinically apparent is correlated with the mechanism of inheritance (see below): X-linked RP, autosomal recessive RP, and autosomal dominant RP generally have their onsets at successively greater ages, although the age ranges overlap considerably. Frequently, a case may present with visual symptoms in late adolescence. Leber congenital amaurosis, an RP allied disease, is a severe congenital retinal dystrophy. Syndromic forms usually present at younger ages than typical cases.

As the retina atrophies, the retinal blood vessels attenuate [1,15]. This, in turn, causes ophthalmoscopically visible changes in the color of the optic nerve head through which the vessels enter the eye.

In summary, a typical case of RP will show atrophy and pigmentary changes to the retina and RPE, early night blindness, loss of the visual fields, loss of central visual acuity, attenuation of the retinal vasculature, and changes to the optic nerve head during the course of the disease. In atypical cases of RP or in the closely related allied diseases, any combination of these symptoms may be altered to a greater or lesser extent. This heterogeneity has, in part, led to the difficulties in consistent clinical classification of the various forms of RP.


Electroretinography

A tool now central to the diagnosis and classification of RP is the electroretinogram (ERG) [15,18-20]. In this procedure, photoreceptor cells are either dark adapted (scotopic ERG) or adapted to a specific level of light (photopic ERG), and then stimulated with a brief flash of light. The summed electrical response of the retina is recorded extraocularly with a contact lens electrode. The scotopic ERG selectively measures the response of the rod photoreceptor cells, while the photopic ERG measures that of the cones. An ERG under dark adapted conditions with stimulation by a sufficiently bright white light flash, the mesopic ERG, measures a response from both types of photoreceptor cells. The initial recorded response of the mesopic ERG is a negative potential reflecting the closure of cyclic nucleotide gated cation channels in the photoreceptor outer segment membrane (see below). Subsequently, the ERG shows a positive displacement reflecting the post-photoreceptor cell neuronal activity [15,20,21]. In typical RP, the rod-cone disease manifests initially as alterations of the scotopic ERG and shows a proportional loss of the photoreceptor cell and post-photoreceptor components of the ERG. With cone-rod dystrophy, photopic ERG changes precede those of the scotopic ERG, but the rod response is eventually affected. In cone dystrophy, the photopic ERG is disrupted while the scotopic ERG remains stable. Retinal degenerations that limit damage to the macula generally damage too few cells to cause a measurable distortion of the ERG. In some cases of RP, the post-photoreceptor cell components of the ERG b-wave are disproportionately disrupted, a circumstance known as a negative, or electronegative, ERG. By the end stages of RP, the ERG responses are extinguished [20,22].


Genetic Classification

Early genetic classifications of RP were derived mainly from the modes of inheritance: autosomal dominant, autosomal recessive, X-linked, or mitochondrial. Cases for which no family history was evident were known as isolate, sporadic, or simplex. With the advents of linkage mapping based on the direct analysis of DNA, of positional cloning, and of the molecular analysis of candidate genes, the description of genetic loci for RP has exploded. There are now 36 known or predicted RP genes (summarized at RetNet), and many more loci for allied diseases and syndromic forms. It has been pointed out that there are over 70 loci that cause photoreceptor dysfunction or degeneration in Drosophila, and a similar number may be expected in humans [23]. In general, RP genes are known or expected to be expressed in the photoreceptor cells of the retina or in the RPE. In the cases of 19 of the RP loci, the precise gene has been described. These known genes can be grouped into several functional classes.

The Visual Cascade

The most common group of genes mutated in RP are those encoding proteins of the visual cascade of the photoreceptor cell outer segment. The visual cascade is the process by which the energy of a photon of visible light is converted into a neuronal signal that is eventually perceived as sight [24]. The cascade begins with the adsorption of light by rhodopsin. Activated rhodopsin stimulates a heterotrimeric G-protein, transducin, that in turn releases the photoreceptor cell specific phosphodiesterase (PDE6) from its inhibitory subunits. The resulting hydrolysis of cGMP allows a cyclic nucleotide gated cation channel in the plasma membrane to close, hyperpolarizing the cells, and transmitting the neuronal signal. The cascade is terminated at several levels, including the phosphorylation of rhodopsin by rhodopsin kinase, the subsequent binding of phosphorylated rhodopsin by arrestin, and by the hydrolysis of bound GTP by the intrinsic GTPase activity of the transducin a subunit.

The genes for the opsin protein of rhodopsin (RHO) [25,26], the catalytic a (PDE6A) [27] and b (PDE6B) [28-30] subunits of PDE6, the a subunit of the rod cyclic nucleotide gated channel (CNGA1) [31], and arrestin (SAG) [32-34] are known to be mutated in cases of RP. Rhodopsin mutations are the most common cause of RP, and account for as many as 1/3 of the 16% of RP cases that are autosomal dominant, as well as rare cases of autosomal recessive RP [1,35]. In addition, several of these genes are mutated in RP-related allied diseases. These include mutations to rhodopsin [36], a transducin (GNAT1) [37], b PDE6 [38], rhodopsin kinase (RHOK) [39], and arrestin [40] in congenital stationary night blindness; to guanylate cyclase activator 1A (GUCA1A) in cone dystrophy type 3 [41]; to the retina-specific guanylate cyclase (GUCY2D) in cone-rod dystrophy type 6 [42,43] and Leber congenital amaurosis type 1 [44]; and to the a subunit of the cone cyclic nucleotide gated cation channel (CNGA3) in rod monochromacy [45]. The three cone opsin genes (blue, BCP; green, GCP; and red, RCP) are mutated in a variety of well described color vision variations and defects [46,47], including occasional progressive cases of macular atrophy [48]. Consistent with the photoreceptor cell specific function of the visual cascade, none of the relevant genes are mutated in syndromic forms of RP.

The Visual Cycle

The second common group of genes mutated in RP are those encoding proteins of the visual cycle. The visual cycle is the series of biochemical steps that provide and recycle the chromophore of rhodopsin, 11-cis-retinaldehyde [49-51]. Vitamin A, all-trans-retinol, is delivered to the RPE from the systemic circulation bound to serum retinol binding-protein. Within the RPE cells, the all-trans-retinol is bound to cellular retinol binding-protein and delivered to lecithin retinol acyltransferase for esterification. Subsequent hydrolysis of the ester bond by an isomerohydrolase provides the energy to isomerize the all-trans-retinol to 11-cis-retinol [52], in a process thought to involve a protein known as RPE65 [53]. The resulting 11-cis-retinol binds cellular retinaldehyde binding-protein (CRalBP), which delivers it to 11-cis retinol dehydrogenase 5 for conversion to 11-cis-retinaldehyde. This molecule is transported extracellularly, possibly on interphotoreceptor retinoid binding-protein [54], taken up by the photoreceptors, and bound to the opsin protein by a protonated Schiff-base linkage [55]. Photoisomerization to all-trans-retinaldehyde initiates the visual cascade discussed above. The all-trans-retinaldehyde, meanwhile, is released from the opsin to the photoreceptor outer segment disc membrane. In rod cells, the released chromophore binds, via a Schiff base linkage, to phosphatidylethanolamine to form N-retinylidene-phosphatidylethanolamine. This substrate is then pumped into the cytoplasm by the ATP-binding cassette transporter of rods (ABCR) [56,57], converted to the alcohol form by a retinol dehydrogenase, and released for transport to the RPE and re-entry into the cycle.

Thus far, the genes encoding RPE65 (RPE65) [58], CRalBP (RLBP1) [59], and ABCR (ABCA4) [60,61] are known to be mutated in RP. In addition, RPE65 has been found to be mutated in some cases of Leber congenital amaurosis [62,63], serum retinol binding-protein (RBP4) is mutated in rare cases of RPE degeneration [64], and the 11-cis retinol dehydrogenase 5 of the RPE (RDH5) is mutated in a form of congenital stationary night blindness known as fundus albipunctatus [65,66]. ABCA4 was first identified as the gene mutated in Stargardt macular dystrophy and fundus flavimaculatus [67], and it has a complex set of mutation phenotypes in addition to classic RP, including both cone-rod and macular dystrophies (for recent reviews see: [7,8,68,69]). Heterozygous ABCA4 mutations have also been implicated in age-related macular degeneration [70,71], although whether these mutations are causal for the disease remains controversial [8]. There are no known syndromic forms of RP due to mutations in visual cascade genes.

The recent description of RP associated mutations in the RPE-retinal G-protein coupled receptor (RGR) [72] opens up new dimensions to the visual cycle and its connection to RP. This seven transmembrane domain receptor, a close relative of rhodopsin, is found in the support cells for the photoreceptors, the RPE and the Muller glia. In antithesis to rhodopsin, the RGR protein is coupled to all-trans-retinal that is isomerized to 11-cis-retinal upon light exposure [73]. Although the role of the RGR in retinal cell biology is not yet clear, it is likely that the proteins in the RPE and Muller glia that deliver vitamin A derivatives specifically to and from this molecule will also be candidates for RP mutations.

Tetraspanins

Two of the known RP genes appear to encode structural proteins of the photoreceptor. These are the genes for peripherin/RDS (RDS) and ROM1 (ROM1), proteins that together form heterotetramers at the margins of the rod outer segment discs [8]. Both of these genes encode 4-transmembrane domain proteins that are divergent members of the tetraspanin superfamily [74]. Mutations in RDS can be directly causal for RP [75,76], but so far the mutations in ROM1 that are definitively pathogenic have occurred only in patients heterozygous for mutations at both RDS and ROM1 (digenic RP) [77,78]. However, the recent description of rod photoreceptor cell loss and outer segment abnormalities in mice with a targeted disruption of Rom1 [79], rekindles the possibility that patients with ROM1 alterations in the absence of RDS mutations may develop RP [80,81]. RDS mutations also have been identified in a variety of macular pattern dystrophies [82,83], and recent reviews more fully describe the complex phenotypic expressions in these cases [3,84].

Tetraspanins as a family form promiscuous associations with many different molecules and appear to function as facilitators of signaling pathways in a number of systems [85]. It is not known if peripherin/RDS and ROM1 have functions other than their described structural roles, but the intrafamilial heterogeneity of clinical symptoms in mutations of either RDS [86-91] or ROM1 [81,92] provides genetic evidence of at least one unknown interacting protein. One potential candidate for these interactions is prominin like-1 (PROM-1), a five transmembrane domain protein that localizes to the evaginating discs of the rod outer segment, and which is mutated in rare cases of autosomal recessive retinal degeneration [93].

Photoreceptor cell transcription factors

The transcription factors NRL (NRL) and CRX (CRX), which synergistically control expression of photoreceptor cell specific genes [94], are known to be mutated in RP [95,96]. The mutations appear both to interfere with photoreceptor cell development and, much later in life, to cause photoreceptor cell degeneration [95-101]. Mutations in CRX have also been implicated as causative in some cases of cone-rod dystrophy [97,99] and Leber congenital amaurosis [95,102]. Recently, the allied disease known as enhanced S cone syndrome has been shown to be caused by mutations in the gene encoding the photoreceptor-specific nuclear receptor (NR2E3) [103], an orphan member of the nuclear receptor superfamily [104]. This disease also has clinical characteristics that indicate both a defect in retinal development, possibly in photoreceptor cell lineage decisions, associated with much later onset photoreceptor cell degeneration [103,105].

Catabolic functions in the retina

Although no defects in catabolism have been specifically noted in RP, several allied diseases and syndromic forms are due to failures to break down metabolites in the retina. Sorsby's fundus dystrophy is due to mutations in the tissue inhibitor of metalloproteinases-3 gene (TIMP-3) [106]. This may lead to altered turnover of the extracellular matrix of the RPE basal lamina, Bruch's membrane. Among syndromic forms of RP, the products of cloned genes for two different Refsum diseases (phytanic acid storage diseases, PEX1 and PHYH) [10] are thought to function in intracellular degradation pathways. Similarly, it has been speculated that the failure of ABCR leads to a build up of undigested vitamin A byproducts within the cells of the RPE in those diseases due to ABCA4 mutations [51,56,57]. The phenotypic variability of the ABCA4 mutations has been proposed to be related to the level of residual ABCR transport activity of the mutant proteins, and the consequently variable level of improperly catabolized substrates [7,57,68,69]. Many additional inborn errors of metabolism causing storage diseases of lipids, carbohydrates, and proteins that include retinal degenerations among their symptoms have also been described and characterized molecularly [15,107].

Mitochondrial genes

A final class of known genes that cause RP are involved in mitochondrial metabolism [108]. Mutations in the mitochondrial genome can cause several conditions in which RP-like symptoms are a feature, although the complexities of mitochondrial genetics lead to substantial variability in symptoms [109]. These diseases include Kearns-Sayre syndrome and a comorbidity of RP in association with deafness that is similar to one form of Usher syndrome [108,110]. The nuclear gene (OAT) for a clinically distinct allied disease, gyrate atrophy, also encodes an enzyme of mitochondrial metabolism, ornithine aminotransferase [111]

Genes of unknown function

Several of the identified RP genes encode products that lack described functions as yet. These include the genes for RP1 (RP1) [112-115], RP2 (RP2) [116], RP3 (retinitis pigmentosa GTPase regulator, RPGR) [117-119], RP12 (crumbs homologue 1, CRB1) [120], and RP14 (tubby-like protein 1, TULP1) [121-123]. The products of the genes for the allied diseases of Best macular dystrophy (vitelliform macular dystrophy, VMD2) [124,125], Doyne honeycomb retinal dystrophy (EGF-containing fibrillin-like extracellular matrix protein 1, EFEMP1) [126], and Leber congenital amaurosis type 4 (aryl-hydrocarbon interacting protein-like 1, AIPL1) [127], and of the Usher syndrome type 2A (USH2A) [128] also have unknown activities. Based on their primary sequence characteristics and/or clinical phenotypes, it seems possible to speculatively cluster some of these proteins into functionally related groups.

Interestingly, the predicted products of RP2 [116], RPGR [129], CRB1 [120], TULP1 [130], and AIPL1 [127], all seem to have features in common with proteins involved in intracellular trafficking. Similarly, the choroideremia (geranylgeranyl transferase Rab escort protein 1, CHM) [131,132] and Usher syndrome type 1B (an unusual myosin, type VIIA, MYO7A) [133] gene products may function in vesicular movement. A second potential grouping of these functionally cryptic proteins is in the metabolism of the extracellular matrix. The RP1 sequence has a series of hyaluronan binding sites [134], and the EFEMP1 [126] and USH2A [128] proteins both have sets of motifs common to extracellular matrix proteins. Finally, a number of these mutated proteins may have features in common with developmental signaling pathways. RP1, for example, has homology to the doublecortin gene (DCX) that is mutated in X-linked lissencephaly and double cortex syndrome [112,113], as well as a possible kinase domain [113]. Recently, TULP1 has been proposed to encode a member of a unique class of transcription factors [135]. Consistent with this possible classification group, the genes for the allied disease congenital stationary night blindness 2 (an a subunit of an L-type voltage-gated calcium channel, CACNA1F) [136,137] and the gene for Alagille syndrome (a Notch ligand, jagged1, JAG1) [138,139] could also function in developmental signal transduction. Although the dual potential functions of RP1 and TULP1 may point towards interactions among these groupings, it remains to be seen whether these proteins will be assembled into functional cascades, as may be suggested by their sequence motifs, or whether they each act independently in retinal cell biology.


Conclusions

In this review, the clinical and electroretinographic fundamentals of retinitis pigmentosa were outlined, and the 19 known RP genes were grouped into functional categories. These genes include: RHO, PDE6A, PDE6B, CNGA1, SAG, RPE65, RLBP1, ABCA4, RGR, RDS, ROM1, PROML1, NRL, CRX, RP1, RP2, RPGR, CRB1, and TULP1. At least 17 additional uncharacterized RP genes are thought to exist by mapping data (summarized at RetNet). Genes mutated in several forms each of Leber congenital amaurosis, cone-rod dystrophy, cone dystrophy, and congenital stationary night blindness, and in a number of syndromes including forms of Bardet-Biedl, Alstrom, Refsum, and Usher syndromes are also uncharacterized (summarized at RetNet). It is important to remember that a number of the known RP genes have been found to be mutated in more than one clinical disease, as, for example, in the cases of RHO, PDE6B, SAG, ABCA4, RDS, and CRX discussed above. This raises the obvious possibility that some of the undescribed RP genes will actually be allelic with some of the undescribed genes for the allied diseases or syndromic forms of RP. It should also be noted that clinically classified diseases are now known to be caused by multiple independent genes, as in the cases of congenital stationary night blindness, cone-rod dystrophy, Leber congenital amaurosis, and classical RP itself. Even clinical subdivisions exhibit surprising genetic heterogeneity, as for example in the RP variant known as retinitis puncatata albescens (Bothnia dystrophy), which has been found to be caused by mutations of the RHO [140], RDS [141], or RLBP1 [142,143] genes. These observations imply that there may be a much greater extent of genetic complexity underlying RP and related ocular diseases than has even yet been appreciated.

No effective approach to prevention, stabilization, or reversal exists for the majority of RP cases. Additionally, in spite of the characterization of so many genes, genetic causes for the majority of cases have yet to be discovered. These facts, therefore, provide an impetus for ongoing research towards two as yet elusive goals: the discovery of the underlying genetic causes of RP in most patients, and therapeutic intervention to halt or reverse the loss of photoreceptor cells. It is hoped that this review will provide some assistance in these twin quests.


Acknowledgements

We would like to thank Dr. Suraj Bhat for productive discussions. This research was supported by National Institutes of Health Grants EY00444 and EY00331 (to D.B.), by a Center Grant from the National Retinitis Pigmentosa Foundation Fighting Blindness Inc., by USPHS National Research Service Award GM07185 (to J.K.P.), and by Dr. James J. and Nancy J. Phelan. D.B. is the Dolly Green Professor of Ophthalmology at UCLA and a Research to Prevent Blindness Senior Scientific Investigator. A preliminary version of this article was included in the doctoral dissertation of J.K.P., entitled "An Analysis of mRNAs Expressed by the Rod Photoreceptor cGMP Phosphodiesterase Alpha and Beta Subunit Genes and by the Duchenne Muscular Dystrophy Gene in the Murine Retina", which was filed 19 November 1999 at UCLA.


References

1. Weleber RG. Retinitis pigmentosa and allied disorders. In: Ryan SJ, editor. Retina. 2nd ed. St. Louis: Mosby; 1994. p. 335-466.

2. Inglehearn CF. Molecular genetics of human retinal dystrophies. Eye 1998; 12:571-9.

3. van Soest S, Westerveld A, de Jong PT, Bleeker-Wagemakers EM, Bergen AA. Retinitis pigmentosa: defined from a molecular point of view. Surv Ophthalmol 1999; 43:321-34.

4. Travis GH. Mechanisms of cell death in the inherited retinal degenerations. Am J Hum Genet 1998; 62:503-8.

5. Fain GL, Lisman JE. Light, Ca2+, and photoreceptor death: new evidence for the equivalent-light hypothesis from arrestin knockout mice. Invest Ophthalmol Vis Sci 1999; 40:2770-2.

6. Perrault I, Rozet JM, Gerber S, Ghazi I, Leowski C, Ducroq D, Souied E, Dufier JL, Munnich A, Kaplan J. Leber congenital amaurosis. Mol Genet Metab 1999; 68:200-8.

7. Rozet JM, Gerber S, Souied E, Ducroq D, Perrault I, Ghazi I, Soubrane G, Coscas G, Dufier JL, Munnich A, Kaplan J. The ABCR gene: a major disease gene in macular and peripheral retinal degenerations with onset from early childhood to the elderly. Mol Genet Metab 1999; 68:310-5.

8. Zack DJ, Dean M, Molday RS, Nathans J, Redmond TM, Stone EM, Swaroop A, Valle D, Weber BH. What can we learn about age-related macular degeneration from other retinal diseases? Mol Vis 1999; 5:30 <http://www.molvis.org/molvis/v5/a30/>.

9. Simunovic MP, Moore AT. The cone dystrophies. Eye 1998; 12:553-65.

10. Verhoeven NM, Wanders RJA, Poll-The BT, Saudubray JM, Jakobs C. The metabolism of phytanic acid and pristanic acid in man: a review. J Inherit Metab Dis 1998; 21:697-728.

11. Carr RE, Heckenlively JR. Hereditary pigmentary degenerations of the retina. In: Tasman W, Jaeger, EA, editors. Clinical Ophthalmology. Vol 3. Philadelphia: Lippencott, Williams, and Wilkins; 1986. p. 1-28.

12. Portera-Cailliau C, Sung CH, Nathans J, Adler R. Apoptotic photoreceptor cell death in mouse models of retinitis pigmentosa. Proc Natl Acad Sci U S A 1994; 91:974-8.

13. Reme CE, Grimm C, Hafezi F, Marti A, Wenzel A. Apoptotic cell death in retinal degenerations. Prog Retin Eye Res 1998; 17:443-64.

14. Zack DJ. Birth and death in the retina: more related than we thought? Neuron 1999; 23:411-2.

15. Heckenlively JR. Retinitis Pigmentosa. Philadelphia: Lippincott; 1988.

16. McGuire RE, Sullivan LS, Blanton SH, Church MW, Heckenlively JR, Daiger SP. X-linked dominant cone-rod degeneration: linkage mapping of a new locus for retinitis pigmentosa (RP 15) to Xp22.13-p22.11. Am J Hum Genet 1995; 57:87-94.

17. Haim M. Prevalence of retinitis pigmentosa and allied disorders in Denmark. II. Systemic involvement and age at onset. Acta Ophthalmol (Copenh) 1992; 70:417-26.

18. Marmor MF, Zrenner E. Standard for clinical electroretinography (1999 update). International Society for Clinical Electrophysiology of Vision. Doc Ophthalmol 1998-99; 97:143-56.

19. Heckenlively JR, Arden GB, editors. Principles and practice of clinical electrophysiology of vision. St. Louis: Mosby Year Book; 1991.

20. Ogden TE. Clinical electrophysiology. In: Ryan SJ, editor. Retina. 2nd ed. St. Louis: Mosby; 1994. p. 321-32.

21. Stockton RA, Slaughter MM. B-wave of the electroretinogram. A reflection of ON bipolar cell activity. J Gen Physiol 1989; 93:101-22.

22. Carr RE. Abnormalities of cone and rod function. In: Ryan SJ, editor. Retina. 2nd ed. St. Louiso: Mosby; 1994. p. 502-14.

23. Dryja TP, Li T. Molecular genetics of retinitis pigmentosa. Hum Mol Genet 1995; 4:1739-43.

24. Stryer L. Visual excitation and recovery. J Biol Chem 1991; 266:10711-4.

25. Dryja TP, McGee TL, Reichel E, Hahn LB, Cowley GS, Yandell DW, Sandberg MA, Berson EL. A point mutation of the rhodopsin gene in one form of retinitis pigmentosa. Nature 1990; 343:364-6.

26. Dryja TP, McGee TL, Hahn LB, Cowley GS, Olsson JE, Reichel E, Sandberg MA, Berson EL. Mutations within the rhodopsin gene in patients with autosomal dominant retinitis pigmentosa. N Engl J Med 1990; 323:1302-7.

27. Huang SH, Pittler SJ, Huang X, Oliveira L, Berson EL, Dryja TP. Autosomal recessive retinitis pigmentosa caused by mutations in the alpha subunit of rod cGMP phosphodiesterase. Nat Genet 1995; 11:468-71.

28. McLaughlin ME, Sandberg MA, Berson EL, Dryja TP. Recessive mutations in the gene encoding the beta-subunit of rod phosphodiesterase in patients with retinitis pigmentosa. Nat Genet 1993; 4:130-4.

29. Danciger M, Blaney J, Gao YQ, Zhao DY, Heckenlively JR, Jacobson SG, Farber DB. Mutations in the PDE6B gene in autosomal recessive retinitis pigmentosa. Genomics 1995; 30:1-7.

30. McLaughlin ME, Ehrhart TL, Berson EL, Dryja TP. Mutation spectrum of the gene encoding the beta subunit of rod phosphodiesterase among patients with autosomal recessive retinitis pigmentosa. Proc Natl Acad Sci U S A 1995; 92:3249-53.

31. Dryja TP, Finn JT, Peng YW, McGee TL, Berson EL, Yau KW. Mutations in the gene encoding the alpha subunit of the rod cGMP-gated channel in autosomal recessive retinitis pigmentosa. Proc Natl Acad Sci U S A 1995; 92:10177-81.

32. Nakamachi Y, Nakamura M, Fujii S, Yamamoto M, Okubo K. Oguchi disease with sectoral retinitis pigmentosa harboring adenine deletion at position 1147 in the arrestin gene. Am J Ophthalmol 1998; 125:249-51.

33. Nakazawa M, Wada Y, Tamai M. Arrestin gene mutations in autosomal recessive retinitis pigmentosa. Arch Ophthalmol 1998; 116:498-501.

34. Yoshii M, Murakami A, Akeo K, Nakamura A, Shimoyama M, Ikeda Y, Kikuchi Y, Okisaka S, Yanashima K, Oguchi Y. Visual function and gene analysis in a family with Oguchi's disease. Ophthalmic Res 1998; 30:394-401.

35. Gregory-Evans K, Bhattacharya SS. Genetic blindness: current concepts in the pathogenesis of human outer retinal dystrophies. Trends Genet 1998; 14:103-8.

36. Dryja TP, Berson EL, Rao VR, Oprian DD. Heterozygous missense mutation in the rhodopsin gene as a cause of congenital stationary night blindness. Nat Genet 1993; 4:280-3.

37. Dryja TP, Hahn LB, Reboul T, Arnaud B. Missense mutation in the gene encoding the alpha subunit of rod transducin in the Nougaret form of congenital stationary night blindness. Nat Genet 1996; 13:358-60.

38. Gal A, Orth U, Baehr W, Schwinger E, Rosenberg T. Heterozygous missense mutation in the rod cGMP phosphodiesterase beta-subunit gene in autosomal dominant stationary night blindness [published erratum appears in Nat Genet 1994; 7:551]. Nat Genet 1994; 7:64-8.

39. Yamamoto S, Sippel KC, Berson EL, Dryja TP. Defects in the rhodopsin kinase gene in the Oguchi form of stationary night blindness. Nat Genet 1997; 15:175-8.

40. Fuchs S, Nakazawa M, Maw M, Tamai M, Oguchi Y, Gal A. A homozygous 1-base pair deletion in the arrestin gene is a frequent cause of Oguchi disease in Japanese. Nat Genet 1995; 10:360-2.

41. Payne AM, Downes SM, Bessant DA, Taylor R, Holder GE, Warren MJ, Bird AC, Bhattacharya SS. A mutation in guanylate cyclase activator 1A (GUCA1A) in an autosomal dominant cone dystrophy pedigree mapping to a new locus on chromosome 6p21.1. Hum Mol Genet 1998; 7:273-7.

42. Kelsell RE, Gregory-Evans K, Payne AM, Perrault I, Kaplan J, Yang RB, Garbers DL, Bird AC, Moore AT, Hunt DM. Mutations in the retinal guanylate cyclase (RETGC-1) gene in dominant cone-rod dystrophy. Hum Mol Genet 1998; 7:1179-84.

43. Perrault I, Rozet JM, Gerber S, Kelsell RE, Souied E, Cabot A, Hunt DM, Munnich A, Kaplan J. A retGC-1 mutation in autosomal dominant cone-rod dystrophy. Am J Hum Genet 1998; 63:651-4.

44. Perrault I, Rozet JM, Calvas P, Gerber S, Camuzat A, Dollfus H, Chatelin S, Souied E, Ghazi I, Leowski C, Bonnemaison M, Le Paslier D, Frezal J, Dufier JL, Pittler S, Munnich A, Kaplan J. Retinal-specific guanylate cyclase gene mutations in Leber's congenital amaurosis. Nat Genet 1996; 14:461-4.

45. Kohl S, Marx T, Giddings I, Jagle H, Jacobson SG, Apfelstedt-Sylla E, Zrenner E, Sharpe LT, Wissinger B. Total colourblindness is caused by mutations in the gene encoding the alpha-subunit of the cone photoreceptor cGMP-gated cation channel. Nat Genet 1998; 19:257-9.

46. Nathans J, Merbs SL, Sung CH, Weitz CJ, Wang Y. Molecular genetics of human visual pigments. Annu Rev Genet 1992; 26:403-24.

47. Neitz M, Neitz J. Numbers and ratios of visual pigment genes for normal red-green color vision. Science 1995; 267:1013-6.

48. Ayyagari R, Kakuk LE, Coats CL, Bingham EL, Toda Y, Felius J, Sieving PA. Bilateral macular atrophy in blue cone monochromacy (BCM) with loss of the locus control region (LCR) and part of the red pigment gene. Mol Vis 1999; 5:13 <http://www.molvis.org/molvis/v5/a13/>.

49. Bok D. Retinal photoreceptor-pigment epithelium interactions. Friedenwald lecture. Invest Ophthalmol Vis Sci 1985; 26:1659-94.

50. Carlson A. Role of cellular retinaldehyde-binding protein and interphotoreceptor retinoid-binding protein in retinoid transport and metabolism in the mammalian retina [dissertation]. Los Angeles: Univ. of California; 1994.

51. Bok D. Photoreceptor "retinoid pumps" in health and disease. Neuron 1999; 23:412-4.

52. Rando RR. Membrane phospholipids as an energy source in the operation of the visual cycle. Biochemistry 1991; 30:595-602.

53. Redmond TM, Yu S, Lee E, Bok D, Hamasaki D, Chen N, Goletz P, Ma JX, Crouch RK, Pfeifer K. Rpe65 is necessary for production of 11-cis-vitamin A in the retinal visual cycle. Nat Genet 1998; 20:344-51.

54. Carlson A, Bok D. Promotion of the release of 11-cis-retinal from cultured retinal pigment epithelium by interphotoreceptor retinoid-binding protein. Biochemistry. 1992; 31:9056-62.

55. Wald G.The molecular basis of visual excitation. Nature. 1968; 219:800-7.

56. Sun H, Molday RS, Nathans J. Retinal stimulates ATP hydrolysis by purified and reconstituted ABCR, the photoreceptor-specific ATP-binding cassette transporter responsible for Stargardt disease. J Biol Chem 1999; 274:8269-81.

57. Weng J, Mata NL, Azarian SM, Tzekov RT, Birch DG, Travis GH. Insights into the function of Rim protein in photoreceptors and etiology of Stargardt's disease from the phenotype in abcr knockout mice. Cell 1999; 98:13-23.

58. Morimura H, Fishman GA, Grover SA, Fulton AB, Berson EL, Dryja TP. Mutations in the RPE65 gene in patients with autosomal recessive retinitis pigmentosa or leber congenital amaurosis. Proc Natl Acad Sci U S A 1998; 95:3088-93.

59. Maw MA, Kennedy B, Knight A, Bridges R, Roth KE, Mani EJ, Mukkadan JK, Nancarrow D, Crabb JW, Denton MJ. Mutation of the gene encoding cellular retinaldehyde-binding protein in autosomal recessive retinitis pigmentosa. Nat Genet 1997; 17:198-200.

60. Martinez-Mir A, Paloma E, Allikmets R, Ayuso C, del Rio T, Dean M, Vilageliu L, Gonzalez-Duarte R, Balcells S. Retinitis pigmentosa caused by a homozygous mutation in the Stargardt disease gene ABCR. Nat Genet 1998; 18:11-2.

61. Cremers FP, van de Pol DJ, van Driel M, den Hollander AI, van Haren FJ, Knoers NV, Tijmes N, Bergen AA, Rohrschneider K, Blankenagel A, Pinckers AJ, Deutman AF, Hoyng CB. Autosomal recessive retinitis pigmentosa and cone-rod dystrophy caused by splice site mutations in the Stargardt's disease gene ABCR. Hum Mol Genet 1998; 7:355-62.

62. Gu SM, Thompson DA, Srikumari CR, Lorenz B, Finckh U Nicoletti A, Murthy KR, Rathmann M, Kumaramanickavel G, Denton MJ, Gal A. Mutations in RPE65 cause autosomal recessive childhood-onset severe retinal dystrophy. Nat Genet 1997; 17:194-7.

63. Marlhens F, Bareil C, Griffoin JM, Zrenner E, Amalric P, Eliaou C, Liu SY, Harris E, Redmond TM, Arnaud B, Claustres M, Hamel CP. Mutations in RPE65 cause Leber's congenital amaurosis. Nat Genet 1997; 17:139-41.

64. Seeliger MW, Biesalski HK, Wissinger B, Gollnick H, Geilen S, Frank J, Beck S, Zrenner E. Phenotype in retinol deficiency due to a hereditary defect in retinol binding protein synthesis. Invest Ophthalmol Vis Sci 1999; 40:3-11.

65. Yamamoto H, Simon A, Eriksson U, Harris E, Berson EL, Dryja TP. Mutations in the gene encoding 11-cis retinol dehydrogenase cause delayed dark adaptation and fundus albipunctatus. Nat Genet 1999; 22:188-91.

66. Gonzalez-Fernandez F, Kurz D, Bao Y, Newman S, Conway BP, Young JE, Han DP, Khani SC. 11-cis retinol dehydroganase mutations as a major cause of the congenital night-blindness disorder known as fundus albipunctatus. Mol Vis 1999; 5:41 <http://www.molvis.org/molvis/v5/a41/>.

67. Allikmets R, Singh N, Sun H, Shroyer NF, Hutchinson A, Chidambaram A, Gerrard B, Baird L, Stauffer D, Peiffer A, Rattner A, Smallwood P, Li Y, Anderson KL, Lewis RA, Nathans J, Leppert M, Dean M, Lupski JR. A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy [published erratum appears in Nat Genet 1997; 17:122]. Nat Genet 1997; 15:236-46.

68. van Driel MA, Maugeri A, Klevering BJ, Hoyng CB, Cremers FP. ABCR unites what ophthalmologists divide. Ophthalmic Genet 1998; 19:117-22.

69. Shroyer NF, Lewis RA, Allikmets R, Singh N, Dean M, Leppert M, Lupski JR. The rod photoreceptor ATP-binding cassette transporter gene, ABCR, and retinal disease: from monogenic to multifactorial. Vision Res 1999; 39:2537-44.

70. Allikmets R, Shroyer NF, Singh N, Seddon JM, Lewis RA, Bernstein PS, Peiffer A, Zabriskie NA, Li Y, Hutchinson A, Dean M, Lupski JR, Leppert M. Mutation of the Stargardt disease gene (ABCR) in age-related macular degeneration. Science 1997; 277:1805-7.

71. Lewis RA, Shroyer NF, Singh N, Allikmets R, Hutchinson A, Li Y, Lupski JR, Leppert M, Dean M. Genotype/Phenotype analysis of a photoreceptor-specific ATP-binding cassette transporter gene, ABCR, in Stargardt disease. Am J Hum Genet 1999; 64:422-34.

72. Morimura H, Saindelle-Ribeaudeau F, Berson EL, Dryja TP. Mutations in RGR, encoding a light-sensitive opsin homologue, in patients with retinitis pigmentosa. Nat Genet 1999; 23:393-4.

73. Hao W, Fong HK. The endogenous chromophore of retinal G protein-coupled receptor opsin from the pigment epithelium. J Biol Chem 1999; 274:6085-90.

74. Wright MD, Tomlinson MG. The ins and outs of the transmembrane 4 superfamily. Immunol Today 1994; 15:588-94.

75. Farrar GJ, Kenna P, Jordan SA, Kumar-Singh R, Humphries MM, Sharp EM, Sheils DM, Humphries P. A three-base-pair deletion in the peripherin-RDS gene in one form of retinitis pigmentosa. Nature 1991; 354:478-80.

76. Kajiwara K, Hahn LB, Mukai S, Travis GH, Berson EL, Dryja TP. Mutations in the human retinal degeneration slow gene in autosomal dominant retinitis pigmentosa. Nature 1991; 354:480-3.

77. Kajiwara K, Berson EL, Dryja TP. Digenic retinitis pigmentosa due to mutations at the unlinked peripherin/RDS and ROM1 loci. Science 1994; 264:1604-8.

78. Dryja TP, Hahn LB, Kajiwara K, Berson EL. Dominant and digenic mutations in the peripherin/RDS and ROM1 genes in retinitis pigmentosa. Invest Ophthalmol Vis Sci 1997; 38:1972-82.

79. Clarke G, Goldberg AF, Vidgen D, Collins L, Ploder L, Schwarz L, Molday LL, Rossant J, Szel A, Molday RS, Birch DG, McInnes RR. Rom-1 is required for rod photoreceptor viability and the regulation of disk morphogenesis. Nat Genet 2000; 25:67-73.

80. Bascom RA, Liu L, Heckenlively JR, Stone EM, McInnes RR. Mutation analysis of the ROM1 gene in retinitis pigmentosa. Hum Mol Genet 1995; 4:1895-902.

81. Sakuma H, Inana G, Murakami A, Yajima T, Weleber RG, Murphey WH, Gass JD, Hotta Y, Hayakawa M, Fujiki K, et al. A heterozygous putative null mutation in ROM1 without a mutation in peripherin/RDS in a family with retinitis pigmentosa. Genomics 1995; 27:384-6.

82. Travis GH, Hepler JE. A medley of retinal dystrophies. Nat Genet 1993; 3:191-2.

83. Keen TJ, Inglehearn CF. Mutations and polymorphisms in the human peripherin-RDS gene and their involvement in inherited retinal degeneration. Human Mutat 1996; 8:297-303.

84. Bird AC. Retinal photoreceptor dystrophies Ll. Edward Jackson memorial lecture. Am J Ophthalmol 1995; 119:543-62.

85. Maecker HT, Todd SC, Levy S. The tetraspanin superfamily: molecular facilitators. FASEB J 1997; 11:428-42.

86. Weleber RG, Carr RE, Murphey WH, Sheffield VC, Stone EM. Phenotypic variation including retinitis pigmentosa, pattern dystrophy, and fundus flavimaculatus in a single family with a deletion of codon 153 or 154 of the peripherin/RDS gene. Arch Ophthalmol 1993; 111:1531-42.

87. Apfelstedt-Sylla E, Theischen M, Ruther K, Wedemann H, Gal A, Zrenner E. Extensive intrafamilial and interfamilial phenotypic variation among patients with autosomal dominant retinal dystrophy and mutations in the human RDS/peripherin gene. Br J Ophthalmol 1995; 79:28-34.

88. Gorin MB, Jackson KE, Ferrell RE, Sheffield VC, Jacobson SG, Gass JD, Mitchell E, Stone EM. A peripherin/retinal degeneration slow mutation (Pro-210-Arg) associated with macular and peripheral retinal degeneration. Ophthalmology 1995; 102:246-55.

89. Jacobson SG, Cideciyan AV, Bascom RA, McInnes RR, Sheffield VC, Stone EM. Variable expression of retinitis pigmentosa in patients with digenic inheritance of peripherin/RDS and ROM-1 gene mutations. Invest Ophthalmol Vis Sci 1995; 36:S913.

90. Richards SC, Creel DJ. Pattern dystrophy and retinitis pigmentosa caused by a peripherin/RDS mutation. Retina 1995; 15:68-72.

91. Jacobson SG, Cideciyan AV, Maguire AM, Bennett J, Sheffield VC, Stone EM. Preferential rod and cone photoreceptor abnormalities in heterozygotes with point mutations in the RDS gene. Exp Eye Res 1996; 63:603-8.

92. Martinez-Mir A, Vilela C, Bayes M, Valverde D, Dain L, Beneyto M, Marco M, Baiget M, Grinberg D, Balcells S, Gonzalez-Duarte R, Vilageliu L. Putative association of a mutant ROM1 allele with retinitis pigmentosa. Hum Genet 1997; 99:827-30.

93. Maw MA, Corbeil D, Koch J, Hellwig A, Wilson-Wheeler JC, Bridges RJ, Kumaramanickavel G, John S, Nancarrow D, Roper K, Weigmann A, Huttner WB, Denton MJ. A frameshift mutation in prominin (mouse)-like 1 causes human retinal degeneration. Hum Mol Genet 2000; 9:27-34.

94. Chen S, Wang QL, Nie Z, Sun H, Lennon G, Copeland NG, Gilbert DJ, Jenkins NA, Zack DJ. Crx, a novel Otx-like paired-homeodomain protein, binds to and transactivates photoreceptor cell-specific genes. Neuron 1997; 19:1017-30.

95. Sohocki MM, Sullivan LS, Mintz-Hittner HA, Birch D, Heckenlively JR, Freund CL, McInnes RR, Daiger SP. A range of clinical phenotypes associated with mutations in CRX, a photoreceptor transcription-factor gene. Am J Hum Genet 1998; 63:1307-15.

96. Bessant DA, Payne AM, Mitton KP, Wang QL, Swain PK, Plant C, Bird AC, Zack DJ, Swaroop A, Bhattacharya SS. A mutation in NRL is associated with autosomal dominant retinitis pigmentosa. Nat Genet 1999; 21:355-6.

97. Freund CL, Gregory-Evans CY, Furukawa T, Papaioannou M, Looser J, Ploder L, Bellingham J, Ng D, Herbrick JA, Duncan A, Scherer SW, Tsui LC, Loutradis-Anagnostou A, Jacobson SG, Cepko CL, Bhattacharya SS, McInnes RR. Cone-rod dystrophy due to mutations in a novel photoreceptor-specific homeobox gene (CRX) essential for maintenance of the photoreceptor. Cell 1997; 91:543-53.

98. Furukawa T, Morrow EM, Cepko CL. Crx, a novel otx-like homeobox gene, shows photoreceptor-specific expression and regulates photoreceptor differentiation. Cell 1997; 91:531-41.

99. Swain PK, Chen S, Wang QL, Affatigato LM, Coats CL, Brady KD, Fishman GA, Jacobson SG, Swaroop A, Stone E, Sieving PA, Zack DJ. Mutations in the cone-rod homeobox gene are associated with the cone-rod dystrophy photoreceptor degeneration. Neuron 1997; 19:1329-36.

100. Furukawa T, Morrow EM, Li T, Davis FC, Cepko CL. Retinopathy and attenuated circadian entrainment in Crx-deficient mice. Nat Genet 1999; 23:466-70.

101. Swaroop A, Wang QL, Wu W, Cook J, Coats C, Xu S, Chen S, Zack DJ, Sieving PA. 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 1999; 8:299-305.

102. Freund CL, Wang QL, Chen S, Muskat BL, Wiles CD, Sheffield VC, Jacobson SG, McInnes RR, Zack DJ, Stone EM. De novo mutations in the CRX homeobox gene associated with Leber congenital amaurosis. Nat Genet 1998; 18:311-2.

103. Haider NB, Jacobson SG, Cideciyan AV, Swiderski R, Streb LM, Searby C, Beck G, Hockey R, Hanna DB, Gorman S, Duhl D, Carmi R, Bennett J, Weleber RG, Fishman GA, Wright AF, Stone EM, Sheffield VC. Mutation of a nuclear receptor gene, NR2E3, causes enhanced S cone syndrome, a disorder of retinal cell fate. Nat Genet 2000; 24:127-31.

104. Kobayashi M, Takezawa S, Hara K, Yu RT, Umesono Y, Agata K, Taniwaki M, Yasuda K, Umesono K. Identification of a photoreceptor cell-specific nuclear receptor. Proc Natl Acad Sci U S A 1999; 96:4814-9.

105. Cepko C. Giving in to the blues. Nat Genet 2000; 24:99-100.

106. Weber BH, Vogt G, Pruett RC, Stohr H, Felbor U. Mutations in the tissue inhibitor of metalloproteinases-3 (TIMP3) in patients with Sorsby's fundus dystrophy. Nat Genet 1994; 8:352-6.

107. Bateman JB, Lang GE, Maumenee IH. Multisystem genetic disorders associated with retinal dystrophies. In: Ryan SJ, editor. Retina. 2nd ed. St. Louis: Mosby; 1994. p. 467-91.

108. Shoffner JM 4th, Wallace DC. Oxidative phosphorylation diseases. Disorders of two genomes. Adv Hum Genet 1990; 19:267-330.

109. Lightowlers RN, Chinnery PF, Turnbull DM, Howell N. Mammalian mitochondrial genetics: heredity, heteroplasmy and disease. Trends Genet 1997; 13:450-5.

110. Mansergh FC, Millington-Ward S, Kennan A, Kiang AS, Humphries M, Farrar GJ, Humphries P, Kenna PF. Retinitis pigmentosa and progressive sensorineural hearing loss caused by a C12258A mutation in the mitochondrial MTTS2 gene. Am J Hum Genet 1999; 64:971-85.

111. Brody LC, Mitchell GA, Obie C, Michaud J, Steel G, Fontaine G, Robert MF, Sipila I, Kaiser-Kupfer M, Valle D. Ornithine delta-aminotransferase mutations in gyrate atrophy. Allelic heterogeneity and functional consequences. J Biol Chem 1992; 267:3302-7.

112. Pierce EA, Quinn T, Meehan T, McGee TL, Berson EL, Dryja TP. Mutations in a gene encoding a new oxygen-regulated photoreceptor protein cause dominant retinitis pigmentosa. Nat Genet 1999; 22:248-54.

113. Sullivan LS, Heckenlively JR, Bowne SJ, Zuo J, Hide WA, Gal A, Denton M, Inglehearn CF, Blanton SH, Daiger SP. Mutations in a novel retina-specific gene cause autosomal dominant retinitis pigmentosa. Nat Genet 1999; 22:255-9.

114. Guillonneau X, Piriev NI, Danciger M, Kozak CA, Cideciyan AV, Jacobson SG, Farber DB. A nonsense mutation in a novel gene is associated with retinitis pigmentosa in a family linked to the RP1 locus. Hum Mol Genet 1999; 8:1541-6.

115. Bowne SJ, Daiger SP, Hims MM, Sohocki MM, Malone KA, McKie AB, Heckenlively JR, Birch DG, Inglehearn CF, Bhattacharya SS, Bird A, Sullivan LS. Mutations in the RP1 gene causing autosomal dominant retinitis pigmentosa. Hum Mol Genet 1999; 8:2121-8.

116. Schwahn U, Lenzner S, Dong J, Feil S, Hinzmann B, van Duijnhoven G, Kirschner R, Hemberger M, Bergen AA, Rosenberg T, Pinckers AJ, Fundele R, Rosenthal A, Cremers FP, Ropers HH, Berger W. Positional cloning of the gene for X-linked retinitis pigmentosa 2. Nat Genet 1998; 19:327-32.

117. Roepman R, Bauer D, Rosenberg T, van Duijnhoven G, van de Vosse E, Platzer M, Rosenthal A, Ropers HH, Cremers FP, Berger W. Identification of a gene disrupted by a microdeletion in a patient with X-linked retinitis pigmentosa (XLRP). Hum Mol Genet 1996; 5:827-33.

118. Meindl A, Dry K, Herrmann K, Manson F, Ciccodicola A, Edgar A, Carvalho MR, Achatz H, Hellebrand H, Lennon A, Migliaccio C, Porter K, Zrenner E, Bird A, Jay M, Lorenz B, Wittwer B, D'Urso M, Meitinger T, Wright A. A gene (RPGR) with homology to the RCC1 guanine nucleotide exchange factor is mutated in X-linked retinitis pigmentosa (RP3). Nat Genet 1996; 13:35-42.

119. Roepman R, van Duijnhoven G, Rosenberg T, Pinckers AJ, Bleeker-Wagemakers LM, Bergen AA, Post J, Beck A, Reinhardt R, Ropers HH, Cremers FP, Berger W. Positional cloning of the gene for X-linked retinitis pigmentosa 3: homology with the guanine-nucleotide-exchange factor RCC1. Hum Mol Genet 1996; 5:1035-41.

120. den Hollander AI, ten Brink JB, de Kok YJ, van Soest S, van den Born LI, van Driel MA, van de Pol DJ, Payne AM, Bhattacharya SS, Kellner U, Hoyng CB, Westerveld A, Brunner HG, Bleeker-Wagemakers EM, Deutman AF, Heckenlively JR, Cremers FP, Bergen AA. Mutations in a human homologue of Drosophila crumbs cause retinitis pigmentosa (RP12). Nat Genet 1999; 23:217-21.

121. Hagstrom SA, North MA, Nishina PM, Berson EL, Dryja TP. Recessive mutations in the gene encoding the tubby-like protein TULP1 in patients with retinitis pigmentosa. Nat Genet 1998; 18:174-6.

122. Banerjee P, Kleyn PW, Knowles JA, Lewis CA, Ross BM, Parano E, Kovats SG, Lee JJ, Penchaszadeh GK, Ott J, Jacobson SG, Gilliam TC. TULP1 mutation in two extended Dominican kindreds with autosomal recessive retinitis pigmentosa. Nat Genet 1998; 18:177-9.

123. Gu S, Lennon A, Li Y, Lorenz B, Fossarello M, North M, Gal A, Wright A. Tubby-like protein-1 mutations in autosomal recessive retinitis pigmentosa. Lancet 1998; 351:1103-4.

124. Petrukhin K, Koisti MJ, Bakall B, Li W, Xie G, Marknell T, Sandgren O, Forsman K, Holmgren G, Andreasson S, Vujic M, Bergen AA, McGarty-Dugan V, Figueroa D, Austin CP, Metzker ML, Caskey CT, Wadelius C. Identification of the gene responsible for Best macular dystrophy. Nat Genet 1998; 19:241-7.

125. Marquardt A, Stohr H, Passmore LA, Kramer F, Rivera A, Weber BH. Mutations in a novel gene, VMD2, encoding a protein of unknown properties cause juvenile-onset vitelliform macular dystrophy (Best's disease). Hum Mol Genet 1998; 7:1517-25.

126. Stone EM, Lotery AJ, Munier FL, Heon E, Piguet B, Guymer RH, Vandenburgh K, Cousin P, Nishimura D, Swiderski RE, Silvestri G, Mackey DA, Hageman GS, Bird AC, Sheffield VC, Schorderet DF. A single EFEMP1 mutation associated with both Malattia Leventinese and Doyne honeycomb retinal dystrophy. Nat Genet 1999; 22:199-202.

127. Sohocki MM, Bowne SJ, Sullivan LS, Blackshaw S, Cepko CL, Payne AM, Bhattacharya SS, Khaliq S, Qasim Mehdi S, Birch DG, Harrison WR, Elder FF, Heckenlively JR, Daiger SP. Mutations in a new photoreceptor-pineal gene on 17p cause Leber congenital amaurosis. Nat Genet 2000; 24:79-83.

128. Eudy JD, Weston MD, Yao S, Hoover DM, Rehm HL, Ma-Edmonds M, Yan D, Ahmad I, Cheng JJ, Ayuso C, Cremers C, Davenport S, Moller C, Talmadge CB, Beisel KW, Tamayo M, Morton CC, Swaroop A, Kimberling WJ, Sumegi J. Mutation of a gene encoding a protein with extracellular matrix motifs in Usher syndrome type IIa. Science 1998; 280:1753-7.

129. Linari M, Ueffing M, Manson F, Wright A, Meitinger T, Becker J. The retinitis pigmentosa GTPase regulator, RPGR, interacts with the delta subunit of rod cyclic GMP phophodiesterase. Proc Natl Acad Sci U S A 1999; 96:1315-20.

130. Hagstrom SA, Duyao M, North MA, Li T. Retinal degeneration in tulp1-/- mice: vesicular accumulation in the interphotoreceptor matrix. Invest Ophthalmol Vis Sci 1999; 40:2795-802.

131. Cremers FP, van de Pol DJ, van Kerkhoff LP, Wieringa B, Ropers HH. Cloning of a gene that is rearranged in patients with choroideraemia. Nature 1990; 347:674-7.

132. Seabra MC, Brown MS, Goldstein JL. Retinal degeneration in choroideremia: deficiency of rab geranylgeranyl transferase. Science 1993; 259:377-81.

133. Weil D, Blanchard S, Kaplan J, Guilford P, Gibson F, Walsh J, Mburu P, Varela A, Levilliers J, Weston MD, et al. Defective myosin VIIA gene responsible for Usher syndrome type 1B. Nature 1995; 374:60-1.

134. Hollyfield JG. Hyaluronan and the functional organization of the interphotoreceptor matrix. Invest Ophthalmol Vis Sci 1999; 40:2767-9.

135. Boggon TJ, Shan WS, Santagata S, Myers SC, Shapiro L. Implication of tubby proteins as transcription factors by structure-based functional analysis. Science 1999; 286:2119-25.

136. Strom TM, Nyakatura G, Apfelstedt-Sylla E, Hellebrand H, Lorenz B, Weber BH, Wutz K, Gutwillinger N, Ruther K, Drescher B, Sauer C, Zrenner E, Meitinger T, Rosenthal A, Meindl A. An L-type calcium-channel gene mutated in incomplete X-linked congenital stationary night blindness. Nat Genet 1998; 19:260-3.

137. Bech-Hansen NT, Naylor MJ, Maybaum TA, Pearce WG, Koop B, Fishman GA, Mets M, Musarella MA, Boycott KM. Loss-of-function mutations in a calcium-channel alpha1-subunit gene in Xp11.23 cause incomplete X-linked congenital stationary night blindness. Nat Genet 1998; 19:264-7.

138. Oda T, Elkahloun AG, Pike BL, Okajima K, Krantz ID, Genin A, Piccoli DA, Meltzer PS, Spinner NB, Collins FS, Chandrasekharappa SC. Mutations in the human Jagged1 gene are responsible for Alagille syndrome. Nat Genet 1997; 16:235-42.

139. Li L, Krantz ID, Deng Y, Genin A, Banta AB, Collins CC, Qi M, Trask BJ, Kuo WL, Cochran J, Costa T, Pierpont ME, Rand EB, Piccoli DA, Hood L, Spinner NB. Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nat Genet 1997; 16:243-51.

140. Souied E, Soubrane G, Benlian P, Coscas GJ, Gerber S, Munnich A, Kaplan J. Retinitis punctata albescens associated with the Arg135Trp mutation in the rhodopsin gene. Am J Ophthalmol 1996; 121:19-25.

141. Kajiwara K, Sandberg MA, Berson EL, Dryja TP. A null mutation in the human peripherin/RDS gene in a family with autosomal dominant retinitis punctata albescens. Nat Genet 1993; 3:208-12.

142. Burstedt MS, Sandgren O, Holmgren G, Forsman-Semb K. Bothnia dystrophy caused by mutations in the cellular retinaldehyde-binding protein gene (RLBP1) on chromosome 15q26. Invest Ophthalmol Vis Sci 1999; 40:995-1000.

143. Morimura H, Berson EL, Dryja TP. Recessive mutations in the RLBP1 gene encoding cellular retinaldehyde-binding protein in a form of retinitis punctata albescens. Invest Ophthalmol Vis Sci 1999; 40:1000-4.


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