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Ocular Phenotype of Bothnia Dystrophy, an Autosomal Recessive Retinitis Pigmentosa Associated With an R234W Mutation in the RLBP1 Gene
Marie S. I. Burstedt, MD;
Kristina Forsman-Semb, PhD;
Irina Golovleva, MD, PhD;
Tomas Janunger, BSc;
Lillemor Wachtmeister, MD, PhD;
Ola Sandgren, MD, PhD
Arch Ophthalmol. 2001;119:260-267.
ABSTRACT
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Objective To describe the phenotype of Bothnia dystrophy, an autosomal recessive
retinal dystrophy with an R234W mutation in the RLBP1
gene encoding cellular retinaldehyde-binding protein.
Design Medical records were reviewed retrospectively. Ophthalmologic examination,
including kinetic perimetry and, in selected cases, adaptometry, color vision
tests, fluorescein angiography, and electrophysiologic studies, was performed.
The study included 24 individuals, all homozygous for an R234W mutation in
the RLBP1 gene.
Results Patients typically show night blindness from early childhood. In young
adults, retinitis punctata albescens was observed, followed by macular degeneration
and a decrease in visual acuity that led to legal blindness in early adulthood.
Dark adaptometry and electrophysiologic testing showed an initial loss of
rod function followed by a progressive reduction of the cone responses in
older ages.
Conclusions Bothnia dystrophy is a unique retinal dystrophy belonging to the rod-cone
dystrophies and has a high prevalence in northern Sweden. Fifty-seven cases
of Bothnia dystrophy have been diagnosed, indicating a prevalence as high
as 1 per 4500 population in the geographic area studied. A defect ability
of mutated cellular retinaldehyde-binding protein to bind retinoid probably
explains the defect rod function followed by central and peripheral degeneration.
Clinical Relevance Retinal dystrophies associated with other mutations of the RLBP1 gene, including retinitis pigmentosa of Bothnia type, might account
for a considerable number of cases of autosomal recessive retinitis pigmentosa
in other geographic areas as well.
INTRODUCTION
RETINITIS PIGMENTOSA (RP) is a group of inherited retinal disorders
with a considerable variation in phenotypic expression and genetic background.
Typical signs of the disease are night blindness and progressive loss of the
peripheral visual field, typical pigment deposition in the retina, attenuation
of the retinal blood vessels, and optic disc pallor. The diagnosis is confirmed
by an abnormal or extinguished electroretinogram (ERG). Examination of records
for patients with RP in the Västerbotten County in northern Sweden has
shown an accumulation of cases with a unique phenotype of RP named Bothnia
dystrophy. Bothnia is the region in northern Sweden west of the Gulf of Bothnia,
historically known as Bothnia Occidentalis. Affected individuals show night
blindness from early childhood, with clinical features consistent with retinitis
punctata albescens (RPA) and macular degeneration. The genetic defect that
causes Bothnia dystrophy was recently shown to reside in the RLBP1 gene mapped to chromosome 15q26,1
encoding the human cellular retinaldehyde-binding protein (CRALBP). The CRALBP
has been localized in retinal pigment epithelium (RPE) and Müller cells
of the retina, ciliary body pigment epithelium, outer epithelium of the iris,
cornea, and optic nerve, and the pineal gland.2-7
In the pigment epithelium, CRALBP functions as a carrier protein for endogenous
retinoids, such as 11-cis-retinol, participating in the visual cycle. 11-Cis-retinol
can either be stored as an ester in the RPE or become oxidized to 11-cis-retinal
by 11-cis-retinol dehydrogenase for visual pigment regeneration and consecutively
recycled back to the outer segment of photoreceptor cells of the retina.8 In vitro studies indicate that the presence of CRALBP
diminishes the esterification and enhances oxidation of 11-cis-retinol.9 Patients affected by Bothnia dystrophy are homozygous
for a C-to-T transition in exon 7 of the RLBP1 gene,
leading to an arginine-to-tryptophan substitution at position 234 of the protein
(R234W).1 Other mutations in the RLBP1 gene have also been identified in patients with autosomal recessive
RP presenting a similar phenotype.10-11
Attempts to define functional domains in CRALBP suggest that a ligand-binding
domain is located in the C-terminal part of the protein between amino acids
120 and 290.12 In this respect, identification
of patients with a mutation in exon 7 of the RLBP1
gene (R234W) is of great interest. The R234W mutation is common in Västerbotten
County, with almost 60 cases already diagnosed. In this study, we report the
clinical and, in selected cases, electrophysiologic findings from 24 cases
with this mutation.
SUBJECTS AND METHODS
SUBJECTS
Twenty patients from Västerbotten County were initially included
in this study, and genetic analysis confirmed that all the affected individuals
were homozygous for the R234W mutation in the RLBP1
gene.1 During the last year, new cases of Bothnia
dystrophy were diagnosed using a polymerase chain reaction (PCR) assay. In
December 1999, the number of cases homozygous for the mutation was 57. Clinical
data from 4 additional cases were therefore added to define the phenotype
more precisely. In addition, 5 unaffected heterozygotes, related to the index
cases, were examined, and 3 of these carriers were subject to electrophysiologic
examinations. The research was performed according to the Declaration of Helsinki
and was approved by the local ethical committee.
GENETIC ANALYSIS
Extraction of genomic DNA was performed as described by Balciuniene
et al.13 Amplification of exon 7 was done by
PCR,1 using nonradioactive primers. Approximately
100 ng of PCR product was subsequently incubated with 0.5 U of MspI restriction enzyme (Boehringer-Mannheim, Mannheim, Germany) at
37° for 3 hours. The restriction endonuclease products were analyzed on
2.5% agarose gel (SeaKem; FMC Bioproducts, Rockland, Me) according to standard
procedures. We took advantage of the fact that the C-to-T transition (C12225T)
(GenBank account No. L34219) in exon 7 eradicates an MspI site. All known nonsyndromic patients with RP in Västerbotten
County were screened for the mutation.
CLINICAL AND FUNCTIONAL INVESTIGATIONS
After retrospective review of medical records of all cases, the patients
were invited to undergo a complete medical eye examination performed by one
of us (M.S.I.B.). Visual acuity (VA), using a Monoyers visual chart, was tested.
Previous results of VA measurements were collected from available medical
records, opticians, and centers for visually disabled. All refractive errors
were converted to spherical equivalents. The VA is presented as logarithm
of minimum angle of resolution (logMAR). The decimal VA was converted into
a log scale using the method outlined by Holladay and Prager.14
The range of VA includes counting fingers, hand motions, and light perception.
For VA less than counting fingers 0.5 m, the following arbitrary logMAR values
were used: counting fingers in front of the eye, logMAR 2.2; hand motions,
logMAR 2.3; and light perception, logMAR 2.5.15
Slitlamp examination, biomicroscopy, and detailed fundus examination
were performed. Visual fields were tested in a Goldmann perimeter using standard
objects in all affected patients. Photographs of the fundi were taken, and
photorecords studied. Fluorescein angiography of the retina was performed
in selected cases, and previously performed angiograms were analyzed. The
course of dark adaptation was determined using a Goldmann-Weekers adaptometer.
Color vision was tested with pseudoisochromatic plates (the Ishihara test
for color blindness, 38 plate edition, 1988) and the Lanthony New Colour rearrangement
tile test in all cases who were able to participate. Electro-oculography and
full-field, single-flash, and flicker ERGs were recorded (UTAS-E 2000; LKC
Technologies Inc, Gaithersburg, Md) using Burian-Allen bipolar electrodes
and according to the recommendations of the International Society of Clinical
Electrophysiological Vision. In dark-adapted conditions, rod responses were
recorded using full-field white flashes of relatively low intensity (24-dB
attenuation). Mixed rod and cone responses were obtained using stimulation
with flashes of maximum intensity (0 dB). Cone responses were elicited in
light adaptation to white background (480 lumen/m2) and using maximum
flash stimulation (0 dB). Flicker ERGs (30 Hz) were recorded in light adaptation
(480 lm/m2) using an averaging technique (n = 10) and stimulation
with maximum-intensity flashes. In 2 of the younger subjects, aged 8 and 15
years, recordings were obtained from only 1 eye because of poor cooperation.
One young patient, aged 9 years, underwent ERG under general anesthesia.
RESULTS
GENETIC ANALYSIS
To correlate the clinical findings with the CRALBP genotype mutation,
all individuals included in our study were tested for the presence of the
R234W mutation. A PCR-based diagnosis method was therefore developed. The
Bothnia dystrophy mutation alters a recognition site for the MspI, and the mutant allele can therefore be distinguished from the
normal allele by MspI cleavage. The results of restriction
endonuclease analysis confirmed that the mutation segregates with Bothnia
dystrophy.
CLINICAL FINDINGS
In most cases the VA shows a progressive decline with age, leading to
legal blindness in the fourth decade of life (Figure 1). However, one 50-year-old woman (case 065:2) with preserved
VA in both eyes represents an exception. Four affected cases, examined since
early childhood, never obtained a VA above 0.2 to 0.3. In one of these subjects
(case 013:2), nystagmus was observed from an early age. In 4 cases, examined
as children, there was an increase in VA as their refractive errors were corrected.
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Figure 1. Visual acuity of the better eye,
expressed as logarithm of minimum angle of resolution (logMAR), related to
age in all 24 patients. Symbols connected by a line are different measurements
on the same patient. Star indicates single observation.
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Fundus examinations revealed no maculopathy of significance in younger
individuals (Table 1). Typical
sub-retinal white dots (RPA) were found in most cases and were first observed
in the teens (Figure 2A).
Signs of maculopathy with central pigment deposits appeared in young adults
(Figure 2B) and later areolar maculopathy
developed (Figure 2C). With increasing
age, round retinal atrophies occurred paracentrally and in the extreme periphery
(Figure 2D). In more advanced stages
of the disease, widespread pigmentations with an appearance similar to bone
spicules could occasionally be found (Figure
2D). Narrowing of the retinal vessels followed advanced retinal
degeneration. However, the optic disc appeared well preserved in all cases
examined. One patient (case 039:2) was treated with miotics because of glaucoma
since the age of 32 years and developed cataract of nuclear type in her 60s.
Ophthalmologic examinations revealed no cataract of significance in any other
subject. The 5 unaffected relatives heterozygous for the mutation showed no
clinical signs of retinal dystrophy.
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Clinical Psychophysical and Electrophysiologic Data of 24 Patients
With Bothnia Dystrophy*
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Figure 2. A, Case 204:1 (17 years old) with
retinitis punctata albescens (RPA). B, Case 222:1 (28 years old) with RPA
and minor maculopathy. C, Case 065:1 (55 years old) with RPA and advanced
maculopathy of areolar type. D, Case 039:1 (71 years old) with round peripheral
atrophies and scattered pigmentary deposits.
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ANGIOGRAPHIC FINDINGS
The fundus photograph and fluorescein angiogram of a young female patient
is presented in Figure 3, A and
B, respectively. The examination was performed 3 years after the electrodiagnostic
evaluation. In the early arteriovenous phase, there was a diffuse hyperfluorescence
in the anatomic macular area and locally in the center of the fovea. Outside
the arcades and corresponding to the atrophic areas in the color fundus photograph,
a general hyperfluorescence of granular type appeared. The hyperfluorescence
indicates a gross atrophy of the pigment epithelium.
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Figure 3. A, Fundus photograph of case 004:5
(16 years old) without signs of maculopathy but peripheral mottling. B, Angiogram
of the same patient as in A, showing an early arteriovenous phase. There is
a general hyperfluorescence of granular appearance outside the arcades and
increased local hyperfluorescence in the fovea.
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PSYCHOPHYSICAL FINDINGS
The visual field was normal in all patients of young age. The visual
fields and the development of defects in one patient (case 005:3), registered
during a period of 23 years, are presented in Figure 4. During the teens, paracentral relative scotomas appeared.
In young adulthood, relatively deeper and larger scotomas, accompanied by
a decrease in VA, evolved. In the fifth decade, absolute extensive scotomas
were present. In older patients, only peripheral islets of the visual fields
remained.
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Figure 4. Progression of visual field defects
in case 005:3. A small central relative scotoma is present in one eye at the
age of 18 years (A). Deeper and larger central-paracentral scotomas developed
with time (B, age 24 years; C, age 28 years). With older age (41 years), absolute
central-paracentral scotomas were present and expanded, finally affecting
the peripheral border (D).
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Color vision, tested with pseudoisochromatic charts, revealed a defect
color sense (2-6 missed plates of 21 tested) in 4 of 5 affected children and
teenagers. However, the test results using the Lanthony New Colour tiles were
normal in these younger patients. In the early 20s, the color sense of the
patients was aggravated and abnormal trichromatism was obtained using the
Lanthony New Colour test. In adulthood, 4 of 5 tested with pseudoisochromatic
plates revealed a grossly defect color sense (20-21 missed plates of 21 tested).
In advanced stages of the disease, it was no longer possible to evaluate the
color vision because of poor VA.
Recovery of dark adaptation showed abnormalities of both rod and cone
function in the 14 patients tested (Figure
5). In the younger patients, the rod function was severely affected
or absent and the cone adaptation abnormal. The final dark-adapted sensitivity
showed an elevation of about 4 log units. In older affected cases, there was
an even more pronounced cone dysfunction. In the most severe stages of the
disease, it was not possible to perform dark adaptometry.
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Figure 5. Results of dark adaptometry in
14 cases aged 8 to 59 years. The blue area indicates the normal range of recovery
of cone and rod sensitivity during dark adaptation for corresponding ages.
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ELECTROPHYSIOLOGIC FINDINGS
Electro-oculography was performed in 8 cases, all of which showed subnormal
electro-oculography ratios (Table 1).
Eighteen subjects underwent electrodiagnostic investigation including ERG.
Representative full-field ERGs from 5 individuals of family 013 are shown
in Figure 6. In the healthy woman
(49 years of age), carrier of the mutation, the ERG showed normal recordings.
In all affected cases (52, 42, 23, and 8 years of age), the rod and the rod-cone
responses were severely reduced. There were no rod or mixed rod-cone responses
recordable in older patients. The amplitudes of the cone B waves were subnormal
and their implicit times prolonged. In the young girl (8 years of age), it
was not possible to obtain reliable flicker ERG recordings. The amplitudes
of the 30-Hz flicker ERGs were within normal limits in the 23-year-old woman
but with increased implicit times. In the older relatives, the amplitudes
of the 30-Hz flicker ERG were severely reduced. In 3 unaffected relatives,
heterozygous for the mutation, normal ERG findings were recorded.
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Figure 6. Dark- and light-adapted electroretinogram
(ERG) responses from a healthy woman (49 years old) and her 2 affected sisters
(cases 013:3 and 013:4) and 2 affected daughters (cases 013:5 and 013:6).
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COMMENT
In this report, a unique clinical phenotype of autosomal recessive RP,
Bothnia dystrophy associated with the R234W mutation in the RLBP1 gene, is described. Severe night blindness is present from early
childhood, with elevated thresholds of dark adaptation early in the course
of the disease. Symptoms of defect macular function with a decrease of VA
appear in early adulthood. Four cases were seen with low VA since childhood,
which could be a manifestation of an early maculopathy. As the disease progresses,
the retinal fundus shows irregular white spots within the retina in a central
and parafoveal pattern along the arcades. With older age, these white spots
diminish and central areolar maculopathy develops. Round circular atrophies
are recorded paracentrally and in the extreme periphery. These atrophies are
reproducible in visual field tests. Fluorescein angiograms in early adulthood
show a widespread hyperfluorescence in the retinal fundus, which indicates
a grossly damaged RPE. In the early teens, most patients had the dark-adapted
rod responses in ERG severely reduced. In all cases, rod-cone and cone responses
were abnormal, although there seems to be a later involvement of the cone
function. Early cases of Bothnia dystrophy may be hard to differentiate clinically
from other variants of autosomal recessive RP until the typical appearance
of RPA and maculopathy occurs.
The fact that RP of Bothnia type segregates with the R234W mutation
in the RLBP1 gene is helpful in confirming clinical
diagnosis. So far, the few published cases10-11
of RP associated with mutations in the RLBP1 gene
have presented with a similar phenotype. Four affected siblings from a consanguineous
family of Indian origin were homozygous for a mutation in exon 5 of the RLBP1 gene (R150Q) and progressed to legal blindness by
their late 20s. Fundus examination showed macular degeneration and small white
dots scattered over the whole fundus. It was shown that recombinant mutant
protein (R150Q) was less soluble than wild-type protein and abolished binding
to 11-cis retinaldehyde.10 Three additional
recessive mutations have been reported in 2 patients belonging to small families
of European ancestry, and those patients demonstrated a phenotype distinguishable
from typical RP. One patient had a mutation located in exon 8, whereas another
patient was a compound heterozygote with mutations in exon 6 and the intron-exon
junction in intron 3.11 Clinical examination
of these 2 cases also showed small yellow deposits at the level of the RPE
across the fundus. In the older patient, there were round areas of atrophic
RPE in the mid and far periphery, similar to our observations in Bothnia dystrophy.
Although a number of polymorphisms scatter over the whole RLBP1 gene,11 the mutations in patients
with RP were found in exons 5, 7, and 8, creating proteins with affected C-terminal
domain of the CRALBP. The significance of the C-terminal part was also shown
by limited proteolysis, demonstrating remained retinoid-binding activity of
the protein without the N-terminal part.16
Thus, only exons 5 to 8 might encode for motives responsible for ligand binding.
The R234W mutation detected in patients with Bothnia dystrophy is in exon
7, and we may expect that mutant protein can significantly differ from the
wild type. R234 is a conserved residue among orthologues to CRALBPs located
close to Q210 and K221, which are shown to be part of the retinoid-binding
pocket.17
A model explaining the phenotype is that the R234W mutation would lead
to lacking ability to bind 11-cis-retinaldehyde, thereby preventing its regeneration
and subsequently a loss of rod function as shown by electrophysiologic testing.
This manifests as elevated thresholds of dark adaptation seen in all patients
independent of duration of the disease. The ability of the mutant R234W protein
to bind retinoid can be tested and will demonstrate whether R234 is involved
in ligand binding. The progressive RPE and photoreceptor cell death manifested
as central and peripheral degeneration might be explained by defect functional
activity of the mutated protein that leads to toxic accumulation of retinoids
in RPE.
At present we have diagnosed almost 60 cases of RP of Bothnia type associated
with recessive mutation R234W in an area with a population of 257 000
inhabitants, and none of them had a diverging clinical appearance. However,
it cannot be excluded that other mutations or combination of mutations (compound
heterozygosity) in the RLBP1 gene could present with
other clinical phenotypes, such as a more classic clinical picture of RP associated
with or without RPA. A variation in clinical phenotype has been reported for
patients with mutations in the ABCR gene. That change
is associated with Stargardt disease but may also cause clinical pictures
that resemble autosomal recessive RP.18 Similar
conditions are well known from the RDS/peripherin gene.19-20
Preliminary data indicate a frequency of patients with Bothnia dystrophy
as high as 1 per 4500 population in Västerbotten County. The difference
in prevalence is striking when compared with the material presented from Boston,
Mass, by Morimura et al.11 In their study of
324 unrelated patients with RP or an allied retinal degeneration, a mutation
in the RLBP1 gene accounted only for 3 cases. An
analysis of blood samples from drafted young men from northern Sweden indicates
a gene frequency as high as 1% to 2% in the population (I.G., unpublished
data, 2000), which makes this condition a medical issue of local great importance.
AUTHOR INFORMATION
Accepted for publication June 22, 2000.
This work was supported by the Swedish Medical Research Council, Stockholm
(projects No. 09745 and 10866), and grants from the County Council of Västerbotten,
Umeå, Carmen and Bertil Regnérs Foundation for Research in the
field of ocular disease, and Crown Princess Margaretha's Foundation for Vision
Research, Stockholm.
Reprints: Ola Sandgren, MD, PhD, Department of Clinical Sciences/Ophthalmology,
University of Umeå, S-901 85 Umeå, Sweden (e-mail: Ola.Sandgren{at}ophthal.umu.se).
From the Departments of Clinical Sciences/ Ophthalmology (Drs Burstedt,
Wachtmeister, and Sandgren) and Medical Biosciences/ Medical Genetics (Drs
Forsman-Semb and Golovleva and Mr Janunger), University of Umeå, Umeå,
Sweden; and Department of Molecular Biology, AstraZeneca, Mölndal, Sweden
(Dr Forsman).
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