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Human Molecular Genetics Advance Access originally published online on June 30, 2004
Human Molecular Genetics 2004 13(17):1893-1902; doi:10.1093/hmg/ddh198
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Human Molecular Genetics, Vol. 13, No. 17 © Oxford University Press 2004; all rights reserved

Nuclear receptor NR2E3 gene mutations distort human retinal laminar architecture and cause an unusual degeneration

Samuel G. Jacobson1,*, Alexander Sumaroka1, Tomas S. Aleman1, Artur V. Cideciyan1, Sharon B. Schwartz1, Alejandro J. Roman1, Roderick R. McInnes2, Val C. Sheffield3,4, Edwin M. Stone3,4, Anand Swaroop5,6,7 and Alan F. Wright8

1Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA 19104, USA, 2Programs in Development and Genetics, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8, 3Department of Pediatrics and 4Department of Ophthalmology, Howard Hughes Medical Institute, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA, 5Department of Ophthalmology, 6Department of Visual Sciences and 7Department of Human Genetics, University of Michigan, Ann Arbor, MI 48105, USA and 8MRC Human Genetics Unit, Western General Hospital, Edinburgh, Scotland

Received April 19, 2004; Accepted June 15, 2004


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 RESULTS
 DISCUSSION
 MATERIALS AND METHODS
 REFERENCES
 
Mutations in the nuclear receptor gene, NR2E3, cause a disorder of human retinal photoreceptor development characterized by hyperfunction and excess of the minority S (short wavelength or blue) cone photoreceptor type, but near absence of function of the majority rod receptor. NR2E3 disease can also progress to blindness. How the human retina accommodates mis-specified types and numbers of neurons and advances to retinal degeneration are unknown. We studied the retinal organization in vivo of patients with NR2E3 mutations. Early human NR2E3 disease with S cone hyperfunction showed thickened retinal layers within an otherwise normally structured retina. With visual loss, however, lamination was coarse and there was a strikingly thick and bulging appearance to the retina, localized to an annulus encircling the central fovea. This pattern was not found in other retinal degenerations. The abnormal laminar retinal architecture of early NR2E3 disease may be due in part to larger cells with an S cone phenotype in place of rods that failed to differentiate. The later-stage dysplastic appearance suggests a previously unrecognized proliferative response in human retinal degeneration.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
RESULTS
 DISCUSSION
 MATERIALS AND METHODS
 REFERENCES
 
The mature human retina is a central nervous system structure with a precisely formed laminar organization. The primary light-sensing visual cells, cones and rods, form the most distal neural layer. The cones (day vision cells) are enriched in the central retina and the rods (night vision cells) are most dense in a ring about 4 mm from the center (1). Spatial topography of the retina has localized thickening and thinning with the underlying mosaics of cells of different type, size and density fitting together to achieve functional neural circuits. This complex adult retinal structure requires a precisely coordinated developmental process, which is increasingly understood at a molecular level (2,3).

The nuclear receptor gene, NR2E3, is postulated to have a role in human rod photoreceptor development (4,5). NR2E3 mutations are associated with an unique autosomal recessive retinal disease, the enhanced S cone syndrome (ESCS). ESCS was first identified when unexpected hyperfunction of the normally minor S (short wavelength sensitive, blue) cone population was found in patients with a severe deficit in rod function (6–8). Proof of greater numbers of photoreceptors with an S cone phenotype in ESCS retinas was provided nearly a decade ago by in vivo electrophysiology (9) and, more recently, by histopathology in a postmortem donor retina of a 77-year-old patient with late-stage ESCS due to NR2E3 mutation (10). Two murine models, the rd7 (Nr2e3 mutant) and the Nrl–/– (with no Nr2e3 expression) mouse, have shown concordant results of increased cone cells and greater percentage with an S cone phenotype (11–13).

How does human retinal structure accommodate mis-specified numbers and types of photoreceptors? With in vivo high-resolution microscopy and correlative measures of vision in patients with NR2E3 mutations, we sought to determine the effects of abnormal NR2E3 on human retinal organization. Architecture of the NR2E3-mutant retina differed remarkably from normal at all disease stages; there were relatively subtle increases in layer thickness as well as surprisingly coarse lamination and regional expansions of retinal tissue. The latter findings suggest a very different retinal degenerative process than previously recognized in man (14).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
DISCUSSION
 MATERIALS AND METHODS
 REFERENCES
 
Retinal topography and lamination are abnormal in the NR2E3-mutant retina
An en face view of the transparent normal human adult retina has obvious features like the optic nerve head and the major vessels coursing along the retinal surface into and out of the nerve (Fig. 1A). En face views of NR2E3-mutant retinas show a multitude of abnormalities including clumps of pigment and atrophic lesions (Fig. 1B and C). Topographical maps of retinal thickness using high-resolution depth (cross-sectional) imaging also show differences between normal (Fig. 1D) and NR2E3-mutant retinas (Fig. 1E and F). The normal retina shows a number of distinctive features: a central depression or foveal pit; a surrounding ring of increased thickness with displaced inner retinal layers from foveal formation; a decline in thickness with distance from the fovea and a prominent crescent-shaped thickening in the nasal retina extending into the superior and inferior poles of the optic nerve, attributable to the converging axons from ganglion cells (Fig. 1D). The topography of NR2E3-mutant retinas also shows a foveal depression, but unlike normal there is a large annular increase in retinal thickness approximately at the eccentricity of the optic nerve; thickness of the annulus is notably greater in superior and inferior retina than along the horizontal meridian in the temporal retina (Fig. 1E and F).



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  		Figure 1. NR2E3-mutant human retinas are abnormally thickened, most prominently in a ring at the eccentricity of the optic nerve. Infrared en face views of the central retina of a representative normal individual, age 22 (A), and two patients (B and C) with NR2E3 mutations (P1, age 32; P2, age 54). White boxes define limits of the topographical map from high-resolution depth imaging in the same individuals, shown to the right. (D) Normal average retinal thickness (n=5; overlaid retinal vessel pattern is from one normal) compared with retinal thickness maps in the NR2E3-mutant retinas (E and F). All images are depicted as right eyes. F, fovea.

 
To probe further the differences between normal and NR2E3-mutant retinal topography, we studied cross-sectional images along horizontal (Fig. 2) and vertical meridia (Fig. 3). The normal human retina in cross-section has a foveal depression and discernible laminae (Fig. 2A). A magnified view of the very central retinal region (box, right) with overlaid reflectivity profiles illustrates the laminar differences between the foveal pit and an adjacent thicker region at 1.7 mm temporal to the fovea. The profile through the pit has a peak at the vitreo–retinal interface, a drop in reflectivity at the nuclear layer and a high multi-peaked reflectivity deep in the retina at the level of cone photoreceptor (PR) inner segments (IS) and outer segments (OS) and retinal pigment epithelium (RPE). At 1.7 mm temporal to the fovea, where rod photoreceptors are numerous, at a density of ~100 000 cells/mm2 (1), the cellular layers of low reflectivity have intervening higher reflectivity laminae that represent synaptic connections. The layer of photoreceptor nuclei [outer nuclear layer (ONL)] averages 62.9 µm in thickness at this location (SD, 5.1 µm; n=8; ages 19–28 years).



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  		Figure 2. Laminar organization of the NR2E3-mutant retina differs from normal and retinitis pigmentosa. Cross-sectional retinal images and visual sensitivities for rods (gray bar; range displayed is from 3.5 to 5.5 log), S cones (blue bar; range from 0 to 3 log) and L cones (red bar; range from 0 to 4 log) along the horizontal meridian from the foveal into the temporal retina. (A) Normal subject (age 26) with full complement of rod and cone vision has a fovea and evident retinal laminae. (B) Retinitis pigmentosa (RP) patient (age 42), with no rod or S cone function but a residual small central island of L cone vision, has a fovea, but there is retinal thinning and poorly defined laminae outside the central region. (C) NR2E3-mutant retina of a 31-year-old patient (P3) with S cone hyperfunction, normal L cone function but no rod function has increased retinal thickening beyond the fovea. (D) NR2E3-mutant retina of a 48-year-old patient (P4) with no rod function but central S cone and L cone function has increased retinal thickenness and coarse lamination beyond the central few millimeter of retina. Magnified cross-sections (white box, green coloration) in the normal subject and patients show details of the more central laminar abnormalities. Reflectivity waveforms are overlaid onto the images at the fovea and at 1.7 mm into the temporal retina. Labels on cross-section are for inner (INL) and outer (ONL) nuclear layers at the 1.7 mm locus. Calibration bars for both sets of images are shown.

 


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  		Figure 3. Cross-sectional images in the vertical meridian in NR2E3-mutant retinas show coarse lamination. (A) Normal cross-sections from superior retina have identifiable laminae and there is a full complement of rod and cone function. (B) Retinitis pigmentosa patient with no measurable vision in this region has a thinned retina with poorly defined laminae. (C–E) NR2E3-mutant retinas with different degrees of S and L cone vision show thickened retina with coarse laminar structure, more pronounced in the retinas with less vision. Magnified cross-sections (white box, green coloration) with overlaid reflectivity waveforms at 4 mm in the superior retina in the five subjects. Calibration bars for both sets of images are shown.

 
A retina affected with retinitis pigmentosa (RP), in contrast to normal, has neither rod nor S cone function; only a central island of reduced L cone function remains (Fig. 2B). The cross-sectional retinal image shows a foveal pit, but the adjacent temporal retina appears thinned compared with the normal. The magnified view (box, right) shows that the foveal reflectivity profile has a vitreo–retinal peak, but the low-reflectivity zone, representing photoreceptor nuclei, is thinned compared with normal. At the 1.7 mm temporal locus, inner retinal lamination is present, but outer retinal layers are abnormal. The low-reflectivity zone representing the ONL is thinned (11.7 µm) and the usual multi-peaked deep high reflectivity has become single-peaked (indicating PR IS/OS signal is reduced but RPE signal is retained) (15–17). The decline in L cone vision with distance from the fovea and the decline in outer retinal layers tend to coincide.

NR2E3-mutant retinas representing two different degrees of disease severity (assayed by amount of cone vision) are shown (Fig. 2C and D). Like the RP retina, there is no measurable rod vision. Unlike RP, NR2E3-mutant retinas (exemplified by P3) can have hyperfunction of S cones, and L cone function at the lower limit of normal. P4 has slightly reduced S cone function and greatly reduced L cone function (7). Both P3 and P4 retain normal-appearing laminar organization in the central 3 mm of retina. The magnified view for P3 (box, right) shows a normal foveal reflectivity profile. At 1.7 mm temporal, inner retinal lamination is intact, but the ONL is thicker than normal (89.7 µm); the PR IS/OS signal is multi-peaked and approximates the normal. Further temporal in P3, the retina does not decline gradually in thickness but becomes reduced at about 3 mm and then remains thicker than the normal. P4 also has a normal foveal reflectivity profile (magnified view not shown), and at 1.7 mm the ONL is normal in thickness (64.5 µm). There are, however, unexpected variations in retinal thickness in the temporal retina. The outer retinal layers taper between the fovea and about 4 mm temporal, somewhat coinciding with the tapering of L cone function. Retinal thickness then increases again (giving the appearance of bulges in the tissue) and lamination becomes indistinct in the region with retained but limited S cone vision. Analyses with high-resolution imaging at 1.7 mm were also performed in two other NR2E3-mutant retinas, and both showed ONL thickness at the upper limit of normal (72–74 µm).

Coarse thickening outside the central retina in NR2E3 mutations
In the vertical meridian of the normal mature human retina (Fig. 3A; about 3–6 mm from the fovea), there are not only neural and synaptic laminae but also ganglion cell axons traversing superficially to converge and exit at the optic nerve, and the retinal arteries and veins. Cross-sectional images in the superior retina show the same laminations and tapering of thickness with distance from the fovea, as along the horizontal meridian (Fig. 2A); the prominent band of high reflectivity near the retinal surface represents the nerve fiber layer (NFL), and retinal surface irregularities are from blood vessels (protrusions into the vitreous that cast ‘shadows’ through the image; Fig. 3A). An RP retina (Fig. 3B), without rod and cone vision in this region, shows dramatic thinning and indistinct lamination. Three NR2E3-mutant retinas with only S and L cone function (Fig. 3C–E), representing progressively decreasing vision, differ from both the normal and the RP retinas by having increased thickness, abnormal lamination and irregularity of the vitreo–retinal surface.

Magnified views of a region expected to have highest rod density (4.4 mm superior to the fovea) (1) are shown with overlaid reflectivity waveforms for each of the five retinas (Fig. 3, right panels). Normal retinal laminae at this location include: the multi-peaked deep signal representing PR IS/OS, RPE and anterior choroid; the alternating cellular and synaptic layers and the NFL (17). In the thinned RP retina, laminae are not easily discernible; there is a single-peaked deep signal (presumed RPE) (15) with enhanced backscatter, a deep hyporeflective and more superficial hyperreflective layer. The NR2E3 retina of P3, with preserved S and L cone function, has a definite laminar organization and is slightly increased in total thickness, compared with the normal. Notable details include: a diminished PR IS/OS peak; normal or slightly increased ONL and INL, and a normal NFL. In addition, the intervening laminae of the depth image appear increased in thickness. NR2E3, P4 and P2 retinas with little or no function in this region have thick coarsely laminated retinas with a single-peaked deep signal (presumed RPE), deep hyporeflective and more superficial hyperreflective layers.

NR2E3 topographical defects are not present in RP and CRX-mutant retinas
To determine whether these observations were specific, we quantified retinal thickness in all 17 patients with NR2E3 mutations (Fig. 4A) and related these data to those of normal subjects (n=18) and two other subgroups of patients with retinal degeneration: five patients with cone-rod dystrophy or Leber congenital amaurosis caused by CRX mutations (Fig. 4B) and 10 patients with RP of unknown genotype (Fig. 4C). NR2E3-mutant retinas (without retinoschisis) can have a foveal depression, but beyond the central retina there is abnormally increased thickness. The patients with CRX mutations, with various severities of dysfunction, all had reduced central retinal thickness, and either normal or reduced thickness beyond the central retina (Fig. 4B) (18). The RP patients showed normal or reduced thickness in the central retina and declining thickness outside the center (Fig. 4C), as anticipated from previous histopathological studies of human RP and in vivo cross-sectional imaging (14,17,18).



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  		Figure 4. Retinal thickness across horizontal (left) and vertical (right) meridia in a group of NR2E3-mutant retinas (A) compared with CRX-mutant retinas (B), and retinitis pigmentosa (RP) of unknown genotype (C). Gray band is the retinal thickness (mean±2SD) in normal subjects. Location of the fovea (F), and directions of temporal (Temp) and inferior (Inf) retina are shown.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
 DISCUSSION
MATERIALS AND METHODS
 REFERENCES
 
Retinal laminar defects in this human disease of a nuclear receptor transcription factor: separating early from late effects
Lamination of the vertebrate retina depends on a complex process in which birth order and cell fate are spatially and temporally coordinated by genes coding for transcription factors, cell cycle regulators and other molecules (2,3,19). The photoreceptor-specific NR2E3 gene is a member of the family of ligand-activated nuclear receptor transcription factors; it is expressed in rod photoreceptors, functioning as a transcriptional activator of rod genes in concert with NRL and CRX (5,20). More than a decade of intense study in animals shows that mutation or misexpression of certain transcription factors can result in defects, which include: (i) failure to specify correctly one or more cell types (13,21–23); (ii) increased formation of alternative cell types (13,22,24–26); (iii) failure to complete differentiation of correctly specified cells (27); (iv) loss of retinal organization (28,29); (v) failure of complete cell cycle exit in abnormally specified cell types (22,24–26,30); and (vi) cell death as a consequence of dysplasia (12,22,30).

Within the context of a dauntingly complex but increasingly understood vertebrate retinogenesis, how do we even begin to explain the striking and different retinal architectural abnormalities in human NR2E3 mutations? On the basis of data from our cohort of patients, we propose a disease sequence with the modest first goal of distinguishing the congenital laminopathy from progressive effects of retinal remodeling and degeneration. Using severity of visual loss and associated laminar changes, we postulate five stages (Fig. 5). Data in support of the sequence were taken from outside the central retina, specifically the inferior retina at about 5 mm from the fovea, in which there is a large range of retinal thickness values among the NR2E3-mutant retinas (Fig. 4A; 219–378 µm; normal range 128–230 µm, n=22). We suggest that stage I represents the congenital laminopathy and stages II–IV represent the progressive aspects of retinal remodeling and degeneration (Fig. 5).



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  		Figure 5. Proposed disease sequence in NR2E3-mutant retinas through four stages (I–IV), on the basis of structure and function measurements in four representative NR2E3-mutant retinas at 5 mm inferior retina. Structure panel (A) shows the thickness and location in depth of the laminated retinal layers [outer nuclear layer (ONL), inner nuclear layer (INL) and nerve fiber layer (NFL)] in a group of normal (N) subjects (n=8) and in P3. Coarsely laminated or unlaminated retina is depicted for P1, P5 and P6 (dark and light grays). Function panel (B) shows L and S cone mediated sensitivities for the same patients at the same retinal location as in the structure panel. Error bars represent +2SD.

 
Stage I (represented by P3, age 31) shows a laminated retina in which some of the layers are abnormally thick (ONL=66 µm, normal=53±5 µm; OPL=41 µm, normal=22±3 µm; IPL+GCL=80 µm, normal 29±4 µm), and there is supernormal S cone function and normal L cone function. Stages II and III (represented by P1, age 31 and P5, age 51) show a coarsely laminated abnormally thick retina with either supernormal or normal S but abnormally reduced L cone function (stage II), or abnormally reduced S and L cone function (stage III). Stage IV (represented by P6, age 77), corresponds to a delaminated retina with near normal thickness, but no measurable visual function. This disease stage is probably similar to that described in the only post-mortem donor retina from a patient with NR2E3 mutation studied by histopathology (10).

Interpreting the human NR2E3 disease sequence in the context of experimental studies
Retained laminar architecture with thickened ONL in stage I NR2E3 disease, taken together with the co-localized vision results of supernormal S, normal L cone and no rod function, leads to the hypothesis that NR2E3 mutation perturbs rod development, specifically rod cell differentiation. Rather than a thinned and disrupted photoreceptor layer from rod cells not forming (23), there is normal or greater thickness of this layer, suggesting a compensatory increase in alternative cells or retained immature ‘rod’ cells expressing S-opsin. Evidence that L cone differentiation was not grossly perturbed comes from our finding of normal structure and function of the L cone-rich foveola (which lacks rod and S cone photoreceptors) (1,31) and normal L cone function at other retinal loci (6–10). The thicker ONL beginning at the foveal edge (Fig. 2) may simply be due to increased cell size. For example, replacement of rod nuclei with cone-like nuclei that are ~15% larger (32) would predict a ~50% increase in ONL layer thickness, assuming random close packing of ellipsoid-shaped nuclei and a packing density that is independent of small size changes (33). In the region of the rod-rich ring of normal retina (1), lamination was retained in stage I NR2E3 disease, but there could be increased thickness of inner as well as outer retinal layers, suggesting cell gain, both in ONL and in secondary and tertiary neurons, as predicted from earlier studies (8,34).

Loss of retinal organization with a coarsely laminated and bulging appearance was a feature of stages II and III of NR2E3 disease and was related to increased visual loss. The topography of this retinal disorganization was an annulus with eccentricity near that of the optic nerve (Fig. 1), a distribution reminiscent of the normal rod-rich ring (1), and possibly marking the location of an earlier stage with high density of cells having S cone phenotype. Interestingly, the two mouse models with Nr2e3 loss of function, rd7 and Nrl–/–, also show postnatal disturbance of retinal organization with variable-sized folds or whorls of S cone cells in the outer retina that precedes degeneration and dysfunction (11–13,35). We offer the following speculative explanations for the retinal disorganization. There could be continued slow proliferation of neuronal (or glial) cells in the NR2E3 deficient retina, resulting in the coarsely laminated bulging human retina and, possibly, the murine whorls. Proliferation may be associated with failure to completely exit the cell cycle (22,23). Alternatively, this is a secondary response to changes in the microenvironment from cell death. For example, release of ciliary neurotrophic factor (CNTF), which can cause proliferation in adult retinal progenitors (36,37), may cause hyperplasia and coarse lamination in regions of greater visual loss in NR2E3-mutant retinas. Photoreceptor degeneration is associated with increased retinal progenitor cell proliferation in the patched (ptc) mouse mutant (with loss of Shh receptor function) (38). The photoreceptor cells with S cone phenotype in NR2E3-mutant retinas have the unusual finding of co-expression of S and L opsin in some of these cones, a property more often seen in fetal cones than adult human cones (10), and may respond differently to neurotrophic activation than cells in other retinal degenerations (Fig. 4B and C).

Stage IV disease in NR2E3-mutant retinas was associated with thinning of the dysplastic-appearing retina and no visual function. Cell death and glial scarring, the likely basis (10), may have several explanations. This may be consistent with the failure of abnormal S cone-like cells to completely exit the cell cycle, which can be associated with apoptosis (30,39,40). In addition, continued proliferation of S cone-like cells could also be followed by a wave of (quasi-developmental) apoptosis, which is not a prominent feature in normal photoreceptor development although it affects other retinal cells (e.g. ganglion cells) (41). Finally, there may be increased sensitivity to cell death of the photoreceptors with S cone phenotype owing to different energy metabolism and oxygen utilization than rods (42,43).

In summary, we propose a disease sequence in which mutations in NR2E3 are associated with a primary phase comprising: (i) failure of rod photoreceptor differentiation; and (ii) a compensatory increase in functional S cone-like cells, associated with thickening of retinal layers. This is followed by a secondary phase comprising: (iii) concomitant loss of retinal lamination and S and L cone function, owing to a combination of cell death and cell proliferation. The thickened and coarsely laminated retinal regions without measurable function may thus be regions with neurons and/or glia reacting to cell death of neighboring L or S cones. This would be a previously unrecognized type of retinal remodeling (14,44) and may be found in other human retinopathies.

Clinical implications of the laminopathies in NR2E3 disease
Are the present results helpful to form future treatment strategies for NR2E3-mutant retinas? The altered cell composition in adult retina resulting from a developmental flaw would not seem approachable, but preventing or slowing the degenerative disease component would be a worthy goal. The finding of coarsely laminated thickened retina in regions of increasing visual loss adds serious complexity. If this is a secondary proliferative process in immature cells following natural cytokine release, there should be concern about use, in these patients, of certain otherwise-promising treatments for retinal degeneration such as CNTF-releasing intraocular drug delivery system (45), now in clinical trials of RP patients. If ESCS-NR2E3 is currently not amenable to treatment, then focus should shift to avoid misdiagnosis of these patients as RP. Relatively simple diagnostic functional tests have been devised for all stages of the disease (46,47) and the ESCS phenotype has been associated with NR2E3 mutation in at least 95% of patients (4,48,49).


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
 DISCUSSION
 MATERIALS AND METHODS
REFERENCES
 
Subjects
Informed consent was obtained from subjects after the nature of all studies had been explained. Research procedures were in accordance with institutional guidelines and the tenets of the Declaration of Helsinki. Molecular diagnoses have been previously published (4,10,18,49,50). Of the 32 participating patients, 17 had NR2E3 mutations (ages 11–77; patients, P, are numbered consecutively by appearance in figures), five had CRX mutations (ages 15–50) and there were 10 patients with retinitis pigmentosa of unknown genotype (ages 29–68). Normal subjects (n=26; ages 4–58) were also included.

Optical coherence tomography: data acquisition
Cross-sectional retinal reflectivity profiles were obtained with optical coherence tomography (OCT) (Zeiss Humphrey Instruments, Dublin, CA, USA) in all 32 patients and in normals. The principles of the method (51) and our techniques (15–18) have been described. Data were acquired with one of two instruments: OCT1 with a theoretical axial resolution in retinal tissue of ~10 µm or OCT3 with a resolution of ~8 µm. Retinal cross-sections were sampled in all patients with vertical and horizontal scan groups centered on the anatomical fovea and consisting of five overlapping segments of linear scans, each 4.5 mm in length, extending 9 mm in either direction. Each segment was repeated at least twice and usually three or more times. In a subset of normals and patients, six scan groups were used to cover a 18x12 mm2 region of the retina centered on the anatomical fovea at high lateral resolution. Each scan group covered a region of 6x6 mm2 of retina by using 21 parallel horizontal (‘raster’) scans of 6 mm length, vertically separated by 0.3 mm. A video fundus image showing the location of the scanned segment was acquired and saved with each OCT scan by the commercial software. In addition, the fundus video visible during the complete session was recorded continuously on a video cassette recorder to allow post-acquisition digitization of fundus images when necessary.

OCT: data analysis
Post-acquisition processing of OCT data was performed with custom programs (MATLAB 6.5, MathWorks, Natick, MA, USA). Longitudinal reflectivity profiles (LRPs) making up the OCT scans were aligned using a dynamic cross-correlation algorithm (15,16) with a manual override when crossing structures (e.g. intraretinal pigment), which interrupted local lateral isotropy by shadowing deeper signals. Spatial maps of retinal thickness were derived from the groups of raster scans. First, the precise location and orientation of each scan relative to retinal features (blood vessels and optic nerve head) were determined using the video images of the fundus. LRPs were allotted to 0.3x0.3 mm2 bins in a rectangular coordinate system centered at the fovea; the waveforms in each bin were aligned and averaged. The retinal thickness, as measured by OCT, was assumed to be the distance between previously defined features T1 (corresponding to the vitreo–retinal interface) and T4 (corresponding to the maximal slope vitread to the signal maximum) on averaged LRPs (15–17,52). Missing data were interpolated bilinearly, thickness values were mapped to a pseudo-color scale, and location of blood vessels and optic nerve head was overlaid for reference. Regions of retinoschisis were excluded manually from the analyses. Highly magnified sections of OCT scans are displayed after using a 2x1 moving median filter to reduce speckle noise in lateral dimension while keeping the original resolution in the longitudinal direction. All data are displayed as equivalent right eyes.

Psychophysics
Psychophysical thresholds were measured (at 2° intervals; stimulus, 1.7° diameter, 200 ms duration) in the same retinal regions as the OCT scans. Rod function was determined using two-color dark-adapted perimetry (500 and 650 nm stimuli). S cone function was measured with 440 nm stimuli on a yellow background (170 cd m–2). Long/middle wavelength sensitive (L) cone function was determined with 650 nm stimuli in the dark-adapted state (6) and compared with the normal data measured during the cone plateau phase of dark adaptation following a bleach. Details of the visual function techniques and analysis methods have been described (4,6–10,34,46,53).


   ACKNOWLEDGEMENTS
 
We thank Anthony Nguyen, Katarzyna Przychodzen, Paul Schied, Elaine Smilko, Elizabeth Windsor, John Chico, Mary Nguyen, Michael Pianta, Alexander Pantelyat, Andy Cheung, Adam Reddick, Marisa Roman and Malgorzata Swider for critical help. This work was supported by grants from the National Institutes of Health, Macula Vision Research Foundation, Foundation Fighting Blindness, F.M. Kirby Foundation, Macular Disease Foundation and Mackall Trust.


   FOOTNOTES
 
* To whom correspondence should be addressed at: Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, 51 N. 39th Street, Philadelphia, PA 19104, USA. Tel: +1 2156629981; Fax: +1 2156629388; Email: jacobsos{at}mail.med.upenn.edu


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
 DISCUSSION
 MATERIALS AND METHODS
 REFERENCES
 

  1. Curcio, C.A., Sloan, K.R., Kalina, R.E. and Hendrickson, A.E. (1990) Human photoreceptor topography. J. Comp. Neurol., 292, 497–523.[CrossRef][ISI][Medline]

  2. Livesey, F.J. and Cepko, C.L. (2001) Vertebrate neural cell-fate determination: lessons from the retina. Nat. Rev. Neurosci., 2, 109–118.[CrossRef][ISI][Medline]

  3. Malicki, J. (2004) Cell fate decisions and patterning in the vertebrate retina: the importance of timing, asymmetry, polarity and waves. Curr. Opin. Neurobiol., 14, 15–21.[CrossRef][ISI][Medline]

  4. Haider, N.B., Jacobson, S.G., Cideciyan, A.V., Swiderski, R., Streb, L.M., Searby, C., Beck, G., Hockey, R., Hanna, D.B., Gorman, S. et al. (2000) Mutation of a nuclear receptor gene, NR2E3, causes enhanced S cone syndrome, a disorder of retinal cell fate. Nat. Genet., 24, 127–131.[CrossRef][ISI][Medline]

  5. Bumsted O'Brien, K.M., Cheng, H., Jiang, Y., Schulte, D., Swaroop, A. and Hendrickson, A.E. (2004) Expression of photoreceptor-specific nuclear receptor NR2E3 in rod photoreceptors of fetal human retina. Invest. Ophthalmol. Vis. Sci., 45, in press.

  6. Jacobson, S.G., Marmor, M.F., Kemp, C.M. and Knighton, R.W. (1990) SWS (blue) cone hypersensitivity in a newly identified retinal degeneration. Invest. Ophthalmol. Vis. Sci., 31, 827–838.[Abstract/Free Full Text]

  7. Jacobson, S.G., Roman, A.J., Roman, M.I., Gass, J.D. and Parker, J.A. (1991) Relatively enhanced S cone function in the Goldmann-Favre syndrome. Am. J. Ophthalmol., 111, 446–453.[ISI][Medline]

  8. Roman, A.J. and Jacobson, S.G. (1991) S cone-driven but not S cone-type electroretinograms in the enhanced S cone syndrome. Exp. Eye Res., 53, 685–690.[CrossRef][ISI][Medline]

  9. Hood, D.C., Cideciyan, A.V., Roman, A.J. and Jacobson, S.G. (1995) Enhanced S cone syndrome: evidence for an abnormally large number of S cones. Vision Res., 35, 1473–1481.[CrossRef][ISI][Medline]

  10. Milam, A.H., Rose, L., Cideciyan, A.V., Barakat, M.R., Tang, W.X., Gupta, N., Aleman, T.S., Wright, A.F., Stone, E.M., Sheffield, V.C. et al. (2002) The nuclear receptor NR2E3 plays a role in human retinal photoreceptor differentiation and degeneration. Proc. Natl Acad. Sci. USA, 99, 473–478.[Abstract/Free Full Text]

  11. Akhmedov, N.B., Piriev, N.I., Chang, B., Rapoport, A.L., Hawes, N.L., Nishina, P.M., Nusinowitz, S., Heckenlively, J.R., Roderick, T.H., Kozak, C.A. et al. (2000) A deletion in a photoreceptor-specific nuclear receptor mRNA causes retinal degeneration in the rd7 mouse. Proc. Natl Acad. Sci. USA, 97, 5551–5556.[Abstract/Free Full Text]

  12. Haider, N.B., Naggert, J.K. and Nishina, P.M. (2001) Excess cone cell proliferation due to lack of a functional NR2E3 causes retinal dysplasia and degeneration in rd7/rd7 mice. Hum. Mol. Genet., 10, 1619–1626.[Abstract/Free Full Text]

  13. Mears, A.J., Kondo, M., Swain, P.K., Takada, Y., Bush, R.A., Saunders, T.L., Sieving, P.A. and Swaroop, A. (2001) Nrl is required for rod photoreceptor development. Nat. Genet., 29, 447–452.[CrossRef][ISI][Medline]

  14. Milam, A.H., Li, Z.Y. and Fariss, R.N. (1998) Histopathology of the human retina in retinitis pigmentosa. Prog. Retin. Eye Res., 17, 175–205.[CrossRef][ISI][Medline]

  15. Huang, Y., Cideciyan, A.V., Papastergiou, G.I., Banin, E., Semple-Rowland, S.L., Milam, A.H. and Jacobson, S.G. (1998) Relation of optical coherence tomography to microanatomy in normal and rd chickens. Invest. Ophthalmol. Vis. Sci., 39, 2405–2416.[Abstract/Free Full Text]

  16. Huang, Y., Cideciyan, A.V., Aleman, T.S., Banin, E., Huang, J., Syed, N.A., Petters, R.M., Wong, F., Milam, A.H. and Jacobson, S.G. (2000) Optical coherence tomography (OCT) abnormalities in rhodopsin mutant transgenic swine with retinal degeneration. Exp. Eye Res., 70, 247–251.[CrossRef][ISI][Medline]

  17. Jacobson, S.G., Cideciyan, A.V., Aleman, T.S., Pianta, M.J., Sumaroka, A., Schwartz, S.B., Smilko, E.E., Milam, A.H., Sheffield, V.C. and Stone, E.M. (2003) Crumbs homolog 1 (CRB1) mutations result in a thick human retina with abnormal lamination. Hum. Mol. Genet., 12, 1073–1078.[Abstract/Free Full Text]

  18. Jacobson, S.G., Cideciyan, A.V., Huang, Y., Hanna, D.B., Freund, C.L., Affatigato, L.M., Carr, R.E., Zack, D.J., Stone, E.M. and McInnes, R.R. (1998) Retinal degenerations with truncation mutations in the cone–rod homeobox (CRX) gene. Invest. Ophthalmol. Vis. Sci., 39, 2417–2426.[Abstract/Free Full Text]

  19. Ohnuma, S., Hopper, S., Wang, K.C., Philpott, A. and Harris, W.A. (2002) Co-ordinating retinal histogenesis: early cell cycle exit enhances early cell fate determination in the Xenopus retina. Development, 129, 2435–2446.[ISI][Medline]

  20. Cheng, H., Khanna, H., Oh, E.C.T., Hicks, D., Mitton, K.P. and Swaroop, A. (2004) Photoreceptor specific nuclear receptor NR2E3 functions as a transcriptional activator in rod photoreceptors. Hum. Mol. Genet., 13, 1563–1575.[Abstract/Free Full Text]

  21. Burmeister, M., Novak, J., Liang, M.Y., Basu, S., Ploder, L., Hawes, N.L., Vidgen, D., Hoover, F., Goldman, D., Kalnins, V.I. et al. (1996) Ocular retardation mouse caused by Chx10 homeobox null allele: impaired retinal progenitor proliferation and bipolar cell differentiation. Nat. Genet., 12, 376–384.[CrossRef][ISI][Medline]

  22. Dyer, M.A., Livesey, F.J., Cepko, C.L. and Oliver, G. (2003) Prox1 function controls progenitor cell proliferation and horizontal cell genesis in the mammalian retina. Nat. Genet., 34, 53–58.[CrossRef][ISI][Medline]

  23. Zhang, J., Gray, J., Wu, L., Leone, G., Rowan, S., Cepko, C.L., Zhu, X., Craft, C.M. and Dyer, M.A. (2004) Rb regulates proliferation and rod photoreceptor development in the mouse retina. Nat. Genet., 36, 351–360.[CrossRef][ISI][Medline]

  24. Ohnuma, S., Philpott, A., Wang, K., Holt, C.E. and Harris, W.A. (1999) p27Xic1, a Cdk inhibitor, promotes the determination of glial cells in Xenopus retina. Cell, 99, 499–510.[CrossRef][ISI][Medline]

  25. Brown, N.L., Patel, S., Brzezinski, J. and Glaser, T. (2001) Math5 is required for retinal ganglion cell and optic nerve formation. Development, 128, 2497–2508.[Abstract/Free Full Text]

  26. Kay, J.N., Finger-Baier, K.C., Roeser, T., Staub, W. and Baier, H. (2001) Retinal ganglion cell genesis requires lakritz, a Zebrafish atonal Homolog. Neuron, 30, 725–736.[CrossRef][ISI][Medline]

  27. Chow, R.L., Volgyi, B., Szilard, R.K., Ng, D., McKerlie, C., Bloomfield, S.A., Birch, D.G. and McInnes, R.R. (2004) Control of late off-center cone bipolar cell differentiation and visual signaling by the homeobox gene Vsx1. Proc. Natl Acad. Sci. USA, 101, 1754–1759.

  28. Wang, S.W., Kim, B.S., Ding, K., Wang, H., Sun, D., Johnson, R.L., Klein, W.H. and Gan, L. (2001) Requirement for math5 in the development of retinal ganglion cells. Genes Dev., 15, 24–29.[Abstract/Free Full Text]

  29. Nakayama, K., Ishida, N., Shirane, M., Inomata, A., Inoue, T., Shishido, N., Horii, I., Loh, D.Y. and Nakayama, K. (1996) Mice lacking p27(Kip1) display increased body size, multiple organ hyperplasia, retinal dysplasia, and pituitary tumors. Cell, 85, 707–720.[CrossRef][ISI][Medline]

  30. Dyer, M.A. and Cepko, C.L. (2001) p27(Kip1) and p57(Kip2) regulate proliferation in distinct retinal progenitor cell populations. J. Neurosci., 21, 4259–4271.[Abstract/Free Full Text]

  31. Yuodelis, C. and Hendrickson, A. (1986) A qualitative and quantitative analysis of the human fovea during development. Vision Res., 26, 847–855.[CrossRef][ISI][Medline]

  32. Hogan, M.J., Alvarado, J.A. and Weddell, J.E. (1971) Histology of the Human Eye. W.B. Saunders, Philadelphia, PA.

  33. Donev, A., Cisse, I., Sachs, D., Variano, E.A., Stillinger, F.H., Connelly, R., Torquato, S. and Chaikin, P.M. (2004) Improving the density of jammed disordered packings using ellipsoids. Science, 303, 990–993.[Abstract/Free Full Text]

  34. Greenstein, V.C., Zaidi, Q., Hood, D.C., Spehar, B., Cideciyan, A.V. and Jacobson, S.G. (1996) The enhanced S cone syndrome: an analysis of receptoral and post-receptoral changes. Vision Res., 36, 3711–3722.[CrossRef][ISI][Medline]

  35. Yanagi, Y., Takezawa, S. and Kato, S. (2002) Distinct functions of photoreceptor cell-specific nuclear receptor, thyroid hormone receptor ß2 and CRX in one photoreceptor development. Invest. Ophthalmol. Vis. Sci., 43, 3489–3494.[Abstract/Free Full Text]

  36. Reh, T.A. (1989) The regulation of neuronal production during retinal neurogenesis. In Finlay, B.F. and Sengelaub, D.R. (eds), Development of the Vertebrate Retina. Plenum, New York, NY, pp. 43–67.

  37. Ezzeddine, Z.D., Yang, X., DeChiara, T., Yancopoulos, G. and Cepko, C.L. (1997) Postmitotic cells fated to become rod photoreceptors can be respecified by CNTF treatment of the retina. Development, 124, 1055–1067.[Abstract]

  38. Moshiri, A. and Reh, T.A. (2004) Persistent progenitors at the retinal margin of ptc+/– mice. J. Neurosci., 24, 229–237.[Abstract/Free Full Text]

  39. Neufeld, T.P. and Edgar, B.A. (1998) Connections between growth and the cell cycle. Curr. Opin. Cell Biol., 10, 784–790.[CrossRef][ISI][Medline]

  40. O'Hare, M.J., Hou, S.T., Morris, E.J., Cregan, S.P., Xu, Q., Slack, R.S. and Park, D.S. (2000) Induction and modulation of cerebellar granule neuron death by E2F-1. J. Biol. Chem., 275, 25358–25364.[Abstract/Free Full Text]

  41. Linden, R., Rehen, S.K. and Chiarini, L.B. (1999) Apoptosis in developing retinal tissue. Prog. Retin. Eye Res., 18, 133–165.[CrossRef][ISI][Medline]

  42. Travis, G.H. (1998) Mechanisms of cell death in the inherited retinal degenerations. Am. J. Hum. Genet., 62, 503–508.[CrossRef][ISI][Medline]

  43. Hoang, Q.V., Linsenmeier, R.A., Chung, C.K. and Curcio, C.A. (2002) Photoreceptor inner segments in monkey and human retina: mitochondrial density, optics, and regional variation. Vis. Neurosci., 19, 395–407.[CrossRef][ISI][Medline]

  44. Marc, R.E., Jones, B.W., Watt, C.B. and Strettoi, E. (2003) Neural remodeling in retinal degeneration. Prog. Retin. Eye Res., 22, 607–655.[CrossRef][ISI][Medline]

  45. Tao, W., Wen, R., Goddard, M.B., Sherman, S.D., O'Rourke, P.J., Stabila, P.F., Bell, W.J., Dean, B.J., Kauper, K.A., Budz, V.A. et al. (2002) Encapsulated cell-based delivery of CNTF reduces photoreceptor degeneration in animal models of retinitis pigmentosa. Invest. Ophthalmol. Vis. Sci., 43, 3292–3298.[Abstract/Free Full Text]

  46. Marmor, M.F., Jacobson, S.G., Foerster, M.H., Kellner, U. and Weleber, R.G. (1990) Diagnostic clinical findings of a new syndrome with night blindness, maculopathy, and enhanced S cone sensitivity. Am. J. Ophthalmol., 110, 124–134.[ISI][Medline]

  47. Milam, A.H. and Jacobson, S.G. (1990) Photoreceptor rosettes with blue cone opsin immunoreactivity in retinitis pigmentosa. Ophthalmology, 97, 1620–1631.[ISI][Medline]

  48. Sharon, D., Sandberg, M.A., Caruso, R.C., Berson, E.L. and Dryja, T.P. (2003) Shared mutations in NR2E3 in enhanced S-cone syndrome, Goldmann–Favre syndrome, and many cases of clumped pigmentary retinal degeneration. Arch. Ophthalmol., 121, 1316–1323.[Abstract/Free Full Text]

  49. Wright, A.F., Reddick, A.C., Schwartz, S.B., Ferguson, J.S., Aleman, T.S., Kellner, U., Jurklies, B., Schuster, A., Zrenner, E., Wissinger, B. et al. (2004) Mutation analysis of NR2E3 and NRL genes in Enhanced S Cone Syndrome. Hum. Mutat., in press.

  50. Miano, M.G., Jacobson, S.G., Carothers, A., Hanson, I., Teague, P., Lovell, J., Cideciyan, A.V., Haider, N., Stone, E.M., Sheffield, V.C. et al. (2000) Pitfalls in homozygosity mapping. Am. J. Hum. Genet., 67, 1348–1351.[ISI][Medline]

  51. Drexler, W., Morgner, U., Ghanta, R.K., Kartner, F.X., Schuman, J.S. and Fujimoto, J.G. (2001) Ultrahigh-resolution ophthalmic optical coherence tomography. Nat. Med., 7, 502–507.[CrossRef][ISI][Medline]

  52. Kijas, J.W., Cideciyan, A.V., Aleman, T.S., Pianta, M.J., Pearce-Kelling, S.E., Miller, B.J., Jacobson, S.G., Aguirre, G.D. and Acland, G.M. (2002) Naturally occurring rhodopsin mutation in the dog causes retinal dysfunction and degeneration mimicking human dominant retinitis pigmentosa. Proc. Natl Acad. Sci. USA, 99, 6328–6333.[Abstract/Free Full Text]

  53. Cideciyan, A.V., Jacobson, S.G., Gupta, N., Osawa, S., Locke, K.G., Weiss, E.R., Wright, A.F., Birch, D.G. and Milam, A.H. (2003) Cone deactivation kinetics and GRK1/GRK7 expression in enhanced S cone syndrome caused by mutations in NR2E3. Invest. Ophthalmol. Vis. Sci., 44, 1268–1274.[Abstract/Free Full Text]


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