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Autosomal Dominant Cone and Cone-Rod Dystrophy With Mutations in the Guanylate Cyclase Activator 1A Gene-Encoding Guanylate Cyclase Activating Protein-1
Susan M. Downes, FRCOphth;
Graham E. Holder, PhD;
Frederick W. Fitzke, PhD;
Annette M. Payne, PhD;
Martin J. Warren, PhD;
Shomi S. Bhattacharya, PhD;
Alan C. Bird, MD
Arch Ophthalmol. 2001;119:96-105.
ABSTRACT
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Objective To describe the phenotype in 3 families with dominantly inherited cone
and cone-rod dystrophy with mutations in guanylate cyclase activator 1A (GUCA1A), the gene-encoding guanylate cyclase activator
protein-1 (GCAP-1).
Methods Phenotypic characterization with psychophysical and electrophysiological
evaluation and confocal laser scanning ophthalmoscopy was performed in 2 families
with a Tyr99Cys mutation and 1 family with a Pro50Leu mutation. Haplotype
analysis was performed in the families with Tyr99Cys mutation.
Results The families with a Y99C mutation were shown to be ancestrally related.
Decreased visual acuity and loss of color vision occurred after the age of
20 years, followed by progressive atrophy of the central 5° to 10°.
Electrophysiological testing revealed generalized loss of cone function, with
preservation of rod function. Abnormal rod and cone sensitivities were confined
to the central 5° to 10°. Confocal laser scanning ophthalmoscopy imaging
showed abnormalities of autofluorescence in early disease. Subjects with a
Pro50Leu mutation demonstrated marked variability in expressivity from minimal
abnormalities of macular function to cone-rod dystrophy.
Conclusions The phenotype associated with the Y99C mutation in GUCA1A is distinctive, with little variation in expression. By contrast,
that associated with the P50L mutation demonstrates
variable expressivity.
Clinical Relevance Phenotype-genotype correlation in these 2 mutations demonstrates 2 different
phenotypes.
INTRODUCTION
CONE DYSTROPHIES are characterized by progressive dysfunction of the
photopic system, with preservation of scotopic function. Autosomal dominant
cone dystrophies have been calculated to occur in approximately 1 in 10 000
live births, with an age-dependent penetrance.1
In cone-rod dystrophy, abnormal rod function may be part of the initial presentation,
but rod involvement may be less severe, or occur later than the cone dysfunction.1-3 The diagnosis is established
by electrophysiological evaluation; functional results depend on the stage
of the disease and the age of the individual.2-5
Common symptoms in cone dystrophy include photophobia and loss of visual
acuity, color vision, and central visual fields.2, 4-5
The retinal appearance may be normal early in disease. With progression, the
retinal pigment epithelium (RPE) may take on a granular appearance and finally
central atrophy. In some cases, temporal atrophy of the optic nerve is present.
Nystagmus is associated with early-onset severe cone dystrophy. Psychophysical
evaluation in cone dystrophy demonstrates loss of central visual fields; recovery
from bleach is monophasic, with a normal final-rod threshold. Color vision
is usually abnormal early in disease with elevation of protan, deutan, or
tritan thresholds or any combination of these.5
In cone-rod dystrophy, function subserved by rods, including visual fields
and night vision, will be variably affected depending on the degree of involvement.
Varying degrees of intraretinal pigment and vessel attenuation occur.
Seven loci have been identified in autosomal dominant cone and cone-rod
dystrophies.6 Those associated with known genes
include chromosome 6p12, with mutations in peripherin/human retinal degeneration
slow (RDS) gene7-10;
chromosome 6p21, with mutations in guanylate cyclase activator 1A (GUCA1A) gene11; chromosome 17p, with
mutations in the retinal guanylate cyclase (GUCY2D)
gene12; and chromosome 19q, with mutations
in cone-rod homeobox (Crx).13
The other loci include 2 in 6q14-15;
a presumed autosomal dominant locus on chromosome 17q in association with
neurofibromatosis16; and 1 in 18q.17 A sporadic case caused by a balanced translocation
between chromosome 1 and 6 has also been recorded.18
The phenotype of 2 families with Tyr99Cys mutations and 1 family with
Pro50Leu were compared, demonstrating that, although these mutations are in
the same gene, the phenotype is different, and, in the case of the Pro50Leu
mutation, shows intrafamilial variability in expression.
SUBJECTS AND METHODS
MOLECULAR ANALYSIS
The methods performed for linkage studies, haplotype analysis, mutation
screening, heteroduplex electrophoresis, and direct genomic sequencing have
been previously described.11, 19
SUBJECTS
Twenty-seven subjects from one 4-generation pedigree (7 affected and
20 unaffected) were recruited to the study (family A). Two further families
were recruited, with 2 members from family B and 3 from family C (Figure 1). Autosomal dominant inheritance
was evident, with affected individuals in each generation and male-to-male
transmission. This research was in accordance with the Declaration of Helsinki
and was approved by the Moorfields Hospital Ethics Committee. Informed consent
was obtained from all participants.
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Figure 1. Pedigree of families A, B, and
C showing generations (roman numerals) of affected (solid symbols) and unaffected
(open symbols) family members. Only relevant members of family A are shown,
as in the genetic article.15
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CLINICAL AND FUNCTIONAL INVESTIGATIONS
Phenotype characterization included an ophthalmic history and fundus
examination. In addition, fundus photography, confocal laser scanning ophthalmoscopy
(cLSO), and psychophysical and electrophysiological evaluations were performed.
ELECTROPHYSIOLOGY
Subjects underwent electrophysiological investigation using techniques
in accord with the recommendations of the International Society for Clinical
Electrophysiology of Vision.20-22
Electro-oculographic responses (EOG), full-field electroretinography (ERG),
and pattern electroretinograms (PERG) were recorded. Depolarizing (ON) and
hyperpolarizing (OFF) responses were recorded using a mini-Ganzfeld stimulator
(CH Electronics, Bromley, England), based on light-emitting diode technology,
using a 120-millisecond, 530-nm stimulus of 440 candelas (cd) per square meter,
on a background of 612-nm and 160 cd/m2, and a stimulus rate of
2 per second.
PSYCHOPHYSICAL TESTS
Static threshold perimetry in the dark- and light-adapted states was
performed using a Humphrey field analyzer (Allergan Humphrey, Hertford, England).
Photopic visual fields were performed using the standard protocol.23-25 For dark-adapted
visual fields, the pupil was dilated with 2.5% phenylephrine hydrochloride
and 1% cyclopentolate hydrochloride, and the patient was dark adapted for
45 minutes. The Humphrey field analyzer was modified for use in dark-adapted
conditions.23-25
An infrared source illuminated the bowl, and an infrared monitor (Phillips,
Eindhoven, Holland) was used to detect eye movements. Fields were recorded
using the central 30-2, peripheral 30/60-2, and macular programs. The target
size corresponded to Goldmann size V for peripheral testing and to Goldmann
size III for macular programs. Each was performed with a red (dominant wavelength,
650 nm) and then blue (dominant wavelength, 450 nm) filter in the stimulus
beam.
The dark-adapted blue central 30-2 fields were reviewed to determine
the most informative locations of dark-adapted visual sensitivity. Two test
locations were chosen at 3° and 9°. The Humphrey field analyzer was
used for dark adaptometry controlled by a custom program on a computer (PS/2
model 50; International Business Machines, Armonk, NY).25-26
Fully dark-adapted rod thresholds were measured before exposure to the adapting
light at the 2 coordinates with the blue filter in the stimulus beam.
For fine matrix mapping, a modified Humphrey field analyzer was used
to present flashes of blue stimuli under scotopic conditions with 4 red light-emitting
diodes in a small diamond configuration for fixation. One hundred positions
on a square 10 x 10 matrix over a 9° x 9° test field were
presented with a Humphrey size III target at 1° intervals. Subsequent
processing of data produced 3-dimensional representation of rod thresholds,
with highest elevations from baseline representing greatest loss of sensitivity.24-26
Color vision was tested using Hardy-Rand-Rittler plates, and color contrast
sensitivity was performed in 3 subjects.27
AUTOFLUORESCENCE IMAGING
Confocal scanning laser ophthalmoscope images of the central macular
region were obtained using a prototype cLSO SM 30-4024, donated by Zeiss (Oberkochen,
Germany). An argon laser (488 nm, 250 µW) was used for illumination.
Reflectance imaging was undertaken using the Zeiss LSO with a 40° field
and the argon blue laser, with the depth plane adjusted to maximize the visibility
of the fundus features. A wide bandpass filter, with a cut-off at 521 nm inserted
in front of the detector, was used to detect autofluorescence, which was recorded,
measured, and analyzed using published techniques.28
RESULTS
DNA ANALYSIS
A GUCA1A mutation in exon 2 of the gene causing
a tyrosine to a cysteine change at position 99 in the protein was identified
in 7 subjects of family A11 and in 4 subjects
in family B. The mutation was found to segregate with disease, and was not
identified in those without the mutation or in 200 "control" subjects. In
family C, a mutation in exon 1 of GUCA1A causing
a proline to a leucine change at position 50 in the protein was identified
in 3 family members. Haplotype analysis of families A and B demonstrated that
these 2 families were ancestrally related. Pedigrees of the 3 families are
shown in Figure 1. The clinical
characteristics of subjects from these families are documented in Table 1.
CLINICAL FINDINGS
Clinical evaluation, including electrophysiology, pyschophysics, and
autofluorescence imaging, was performed in family A before the results of
the genetic analysis were known. Affected members of family A became symptomatic
in their late 20s with very minimal photophobia and reduced central vision.
The visual deficit, even in the oldest subject (age 88 years), was confined
to the central vision, with no peripheral field loss, and visual acuities
of counting fingers. Mild RPE granular changes were seen in the presymptomatic
16-year-old subject A IV/2 (Figure 2A-B),
and white deposits were noted in at the maculae of subjects A III/2 and A
II/11 (Figure 2C-D). Finer, less
obvious, white deposits were also noted in A III/4 and A II/9. Central atrophy
was noted in all subjects, apart from subject A IV/2 (Figure 2A, B, D, and E). This became more pronounced with age, apart
from subject A II/9, in whom a milder phenotype was observed. No abnormalities
were observed outside the macular region in any member. In family B, subject
B IV/1 (aged 32 years), with visual acuity of 20/200 OU, had been symptomatic
since her early 20s, with mild photophobia and poor central vision. Fundus
examination revealed symmetrical parafoveal RPE granular abnormalities distributed
in a limited bull's eye–type pattern (Figure 2G). Fluorescein angiography findings corresponded to the
bull's eye–type appearance seen on fundus examination (Figure 1 2G-I). Her father was diagnosed as affected with a central
dystrophy in late childhood with similar symptoms. Both her brothers were
reported by the family to have similar difficulties and were found to have
the mutation.
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Figure 2. A, Macula of right eye of subject
A IV/2, showing no obvious abnormality. B, Increased autofluorescence signal
parafoveally, with an annulus of decreased autofluorescence in same eye of
same subject. C, Macular atrophy in right eye of subject A II/11, with white
deposits surrounding the atrophic area. D, Increased autofluorescent signal
surrounding the central area of decreased autofluorescence in area of atrophy
in same subject. E, Atrophic macula and surrounding normal retinal appearance
in subject A II/1. F, Same area showing markedly decreased levels of autofluorescence
in the area of atrophy and high autofluorescence at edge of atrophy. G, Right
macula of subject B III/1 showing central retinal thinning. H, Fluorescein
angiogram in same subject showing central masking, presumed to be caused by
lipofuscin deposition (corresponding to bright signal of increased autofluorescence),
and hyperfluorescence caused by loss of retinal pigment epithelium of central
retina (corresponding to decreased autofluorescent signal on confocal laser
scanning ophthalmoscopy). I, Confocal laser scanning ophthalmoscopy imaging
showing increased autofluorescence at right macula. J, Right macula of subject
C III/2 showing early atrophy and abnormalities of the retinal pigment epithelium.
K, Autofluorescence imaging of same eye of same subject C III/2, showing band
of autofluorescence surrounding the area of early atrophy seen on funduscopy.
L, Showing similar findings in the left eye of the same subject. M, Right
macula of subject C III/10, showing atrophy and intraretinal bone-spicule
pigmentation. N, Showing peripheral view of right eye with intraretinal bone
spicule pigmentation. O, Autofluorescence imaging of same eye of same subject
showing massive deposition of autofluorescent material within the macula.
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In family C, variability of expression was seen. Subject C III/2 had
onset of his symptoms in his late 30s, with photophobia and reduced central
vision but normal peripheral visual fields and visual acuity of 20/40 OU by
the age of 43 years. Central RPE granular changes were noted (Figure 2J-I). Subject C II/3, his aunt, only began to be symptomatic
in her mid-50s, with mild photophobia. Her visual acuity was 20/30 OU. Her
son, C II1/10, had a completely different phenotype with nyctalopia, moderate
photophobia, and some reduction of his central vision since his late 20s,
with visual acuities of 20/60 OD and 20/40 OS by the age of 35 years. His
visual fields were constricted to a central 5°, and typical peripheral
intraretinal bone-spicule pigmentation was observed. (Figure 2M-O). Clinical characteristics are documented in Table 1.
ELECTROPHYSIOLOGY
Electrophysiological tests were performed in 7 affected subjects from
family A, 2 from family B, and 3 from family C.
Family A
The EOG light rise was normal in each subject; in 2 affected subjects,
the rises were particularly high (>370% in 4 eyes, with 3 being  400%).
Pattern electroretinograms were recorded in all subjects (Figure 3A). In subject A IV/2, the
P50 component was normal in the right eye, but significantly lower than the
left. In subject A II/9 it was still recordable, although markedly reduced
in amplitude, but her son, subject A III/2, showed only minimal residual PERG
activity. In the remaining subjects, the PERG was extinguished. Scotopic ERGs,
including the rod-specific response and the bright white–flash ERG,
were normal in 6 of 7 members in family A (Figure 3 B-C). The oldest member, A I/1, aged 88 years, had a low
rod ERG b-wave amplitude, but this was within normal limits for age. The rod
ERG b-wave of his son, A II/1, was of borderline amplitude, but normal implicit
time (Figure 3B). The photopic ERG
showed decreased b-wave amplitude, with no increase in implicit time in 6
symptomatic subjects, but a normal response in the asymptomatic A IV/2 (Figure 3D). The 30-Hz flicker ERG was reduced
in symptomatic subjects, but, however small, showed no shift in implicit time
(Figure 3E). Both ON and OFF responses
were reduced in 6 of 6 patients in whom the test was abnormal. No abnormality
was present in the asymptomatic A IV/2 (Figure
3F). The findings in A II/11 differ in that the ON response was
delayed, and the OFF response was markedly reduced.
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Figure 3. A, Pattern electroretinograms
(PERGs) of family A. In subject II/9, the P50 component is grossly reduced.
Her son, subject III/2, shows only residual activity. In all subjects, other
than A V/2, the PERG is extinguished. B, Scotopic-rod electroretinograms (ERGs)
show no definite abnormality for age. C, Maximal ERGs (bright white–flash,
dark-adapted) show no definite abnormality. D, 30-Hz flicker ERGs are normal
in II/2, II/4, and IV/2, but markedly reduced in the other subjects. No increase
in implicit time is present. E, Photopic ERG showing decreased b-wave amplitude
in all subjects, apart from subject IV/2, in whom there is no abnormality.
No subject shows implicit time increase. F, Depolarization (ON) and hyperpolarization
(OFF) responses. No abnormality was present in the asymptomatic A IV/2. The
other subjects show reduction in both ON and OFF responses. Subject A II/11
differs in that the ON response is delayed and the OFF response is more markedly
reduced. G, Electrophysiology of mother (C II/3) and son (C III/10) of family
C, showing reduction of the PERG in C II/3, mild increase in 30-Hz flicker
implicit time, but otherwise normal evaluation. The son has, by contrast,
extinguished PERGs, gross reduction in the rod-specific b-wave amplitude,
marked reduction of both a- and b-wave amplitudes in the bright white–flash
responses, and grossly delayed and reduced amplitudes of his 30-Hz flicker
and photopic ERG.
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Family B
In subject B IV/1, aged 32 years, the PERG was extinguished. The EOG
was normal, and full-field ERGs were normal to all stimuli. In particular,
photopic and flicker were of normal amplitudes and normal implicit times.
Her father had had an ERG in 1980 that showed significantly reduced cone activity.
Family C
The electrophysiology of the proband C III/2 was not performed according
to International Society for Clinical Electrophysiology of Vision standards,
but a normal EOG light rise and normal rod electrophysiology were obtained.
His PERG was extinguished bilaterally, and just as in family A, photopic and
flicker ERG responses showed reduced amplitudes but no increase in implicit
times. In his aunt, C II/3, the PERG was reduced bilaterally and there was
a very slight increase in the implicit time of the 30-Hz flicker ERG; however,
the scotopic ERG and EOG were normal. In her son, C III/10, the PERG was extinguished
bilaterally, there was no EOG light rise, full-field ERGs showed severe reduction
in rod-specific b-wave amplitude, and there was marked reduction in both a-
and b-wave amplitudes in the bright white–flash responses. His 30-Hz
response was markedly delayed with moderately severe amplitude reduction.
The photopic ERG was markedly reduced and delayed (Figure 3G).
PSYCHOPHYSICS
Families A and B
In family A, loss of sensitivity confined to the central 5° to 10°
was seen, particularly in subjects A II/1, A II/11, and A III/4. In these
3 subjects, severe sensitivity loss of 10 to 20 dB with an absolute scotoma
was identified. Subjects A II/9 and A III/2 (mother and son) and subjects
A IV/2 and B III/1 had minimal loss of sensitivity. Dark-adapted red and blue
perimetry also demonstrated decreased sensitivity to cone and rod stimuli
(Figure 4A).
Similar findings were seen in subjects B III/2 and B IV/1.
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Figure 4. A, Photopic and dark adapted scotopic
red and blue 30° static perimetry showing central loss of both cone and
rod sensitivities centrally in subject A II/1, aged 58 years. B, Fine matrix
mapping to show marked sensitivity losses superior to fixation with nearly
normal measurements below fixation in subject A II/1 (aged 58 years). C, Fine
matrix mapping in subject A III/4 (aged 42 years) showing less marked sensitivity
losses. D, Fine matrix mapping in subject A IV/2 (aged 16 years) showing minimal
sensitivity loss.
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Fine matrix mapping was performed in family A and demonstrated areas
of elevated thresholds even in subject A IV/2, in whom nearly normal sensitivity
was observed. The central threshold elevation was primarily due to the normal
rod-free zone of the fovea (Figure 4B-D).
The older subjects had greater losses of sensitivity, although once again
subject A II/9 exhibited a milder phenotype. Dark adaptation was recorded
in A II/11, A III/2, A III/4, and A IV/2. In these subjects, the cone plateau,
the rod-cone break, and the rate of recovery of the rod portion of the dark-adaptation
curve fell within the normal range (Figure
5).
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Figure 5. Dark-adaptation curve in subject
A II/11, showing that the kinetics of sensitivity and recovery fall within
the normal range.
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Hardy-Rand-Ritler color plate testing was abnormal in all affected subjects,
apart from A IV/2, and color-contrast sensitivity, performed in subjects A
III/4, A IV/2, and B IV/1, demonstrated marked elevation of threshold in all
3 axes in A III/4 and thresholds at the upper limit of normal in his 16-year-old
daughter (subject A IV/2); thresholds for all 3 axes were elevated in both
eyes of subject B IV/1.
Family C
Subject C III/2 had losses in sensitivity confined to the central 5°
to 9°, with no peripheral abnormalities on photopic testing. Subject C
II/3 showed relatively normal photopic function throughout the central 30°,
with gradual increasing cone sensitivity losses in the periphery (Figure 6A).
Rod sensitivity was within 1.0 log unit of normal throughout the central retina,
with no clear-rod sensitivity loss for most of the visual field. Her son (subject
C IV/10) showed profound photopic sensitivity losses of more than 3.0 log
units throughout most of the central 30° with a small foveal region of
spared function. Extensive regions of reduced but abnormal cone sensitivity
were observed peripheral to 30° (Figure
6B). Rod function showed a similar pattern of midperipheral sensitivity
loss, with profound losses of more than 4.0 log units in the central region
and relatively good rod function within 2.0 log units of normal extending
from about 30° out to the far periphery in the inferior nasal field (Figure 6C).
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Figure 6. A, Scotopic 30° and 60°
combined fields of subject C II/3, showing relatively normal scotopic function
throughout the central 30°, with gradually increasing cone-sensitivity
losses in the periphery. B, Photopic 30° and 60° combined fields of
subject C III/10, showing profound losses of photopic sensitivity of more
than 3 log units throughout most of the 30°, with a small foveal region
of spared function. Extensive regions of reduced cone sensitivity were seen
peripheral to 30°. C, Scotopic 30° and 60° combined fields in
same subject demonstrating profound rod sensitivity losses of more than 4
log units in the central region with better rod function from 30° to the
periphery.
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AUTOFLUORESCENCE IMAGING
In family A, localized increased autofluorescence was observed centrally
with a surrounding annulus of decreased autofluorescence. Asymptomatic subject
A IV/2 showed increased levels of autofluorescence at the fovea, with little
to see on funduscopy (Figure 2B).
In the older subjects, the area of decreased autofluorescence was more extensive,
but still localized to the central area. A high level of autofluorescence
surrounded the area of atrophy (Figure 2I). In subject A III/2, discrete areas of high autofluorescence corresponded to
white deposits seen in the fundus. This was also seen to a lesser extent in
subject A II/11 (Figure 2D). In
family B, only subject B IV/1 had imaging performed. The fluorescein angiogram
showed hyperfluorescence corresponding very closely to the area where decreased
levels of autofluorescence were observed, presumably in this case because
of loss of RPE pigment and early atrophy (Figure 2I). There is again an increased fringe of autofluorescence
around the perimeter of the lesion (Figure
2J). In family C, subject C III/2 showed a clear annulus of autofluorescence
similar to that seen in family A in older subjects, but broader in width (Figure 2 K and L). His aunt, subject C II/3,
showed no abnormality, but her son (subject C II/10) had a massive increase
in autofluorescence at both maculae, but none peripherally (Figure 2O).
COMMENT
This study is, to our knowledge, the first to document the phenotype
associated with 2 mutations in a gene only recently described as disease-causing.11 The phenotype seen in the Y99C mutation is highly
distinctive, with detectable abnormal function and autofluorescence occurring
before either symptoms or obvious ophthalmoscopic changes, and only mild variation
in phenotype. Although the fundus features evolving from granular RPE changes
at the macula to frank atrophy in the older individuals is fairly typical
for a cone dystrophy, the electrophysiology seen in this mutation is distinctive.
Cone dystrophies are associated with increased implicit times and decreased
amplitudes in the cone-specific responses.2-5
However, in this family, no increase in implicit time was seen, despite reduced
amplitudes in the 30-Hz flicker and photopic ERG responses. The electrophysiology
is not well described by using the classification of Szylek et al,29 as this distinguishing feature is lost. However,
according to this classification, the Y99C dystrophy would be categorized
as a type 1a. The lack of preferential loss of color vision is unlike the
cone degenerations described by Weleber and Eisner,30
in which the most common color defect was shown to be the green-red type.
Other clinical studies have highlighted particular color deficits, as in a
4-generation family with autosomal dominant cone dystrophy described by Went
et al,31 in which the characteristic features
are a decline in vision after the age of 20 years, with a near complete absence
of blue-cone function before any ophthalmological abnormality.
Fishman et al10 describe a cone dystrophy
in a family with S27F mutation in peripherin/RDS.
The electrophysiology described in their family with 3 affected members is
very similar to that seen in the Y99C GUCA1A family.
Specifically, their family has normal rod responses, and reduction in the
cone-specific ERG amplitudes, but no increase in implicit times. However,
the cone degeneration described in this study seems to be milder regarding
visual acuity and psychophysics testing than the families with a Y99C mutation.
In addition, the 77-year-old in their study with a codon S27F mutation has no central atrophy, unlike the marked central atrophy
noted in the Y99C GCAP-1 mutation at a comparable age. It is also of note
that 2 other members of this same family had a different sequence change in
peripherin/RDS and did not have disease. On the basis
of the electrophysiology, it would be interesting perform mutational analysis
for a Y99C mutation in GUCA1A in this family.
The phenotype in the family with the P50L mutation in GUCA1A is quite different, with marked variation in expressivity. In
this family, all 3 affected subjects manifested a different phenotype with
minimal macular involvement with mild symptoms, a cone dystrophy, with the
same phenotype as seen in the Y99C mutation, and a moderately severe cone-rod
dystrophy classifiable under the Szylek system as a type 2b. This marked variation
in expression is not so extreme as that seen in the peripherin/RDS codon 153/4 mutation.32 Variable
expressivity has been reported in autosomal dominant RP associated with loci
7p and 19q.33-34 There is also
a precedent for a members of a family to demonstrate a more severe phenotype,
despite having the same mutation.35 Secondary
factors, such as deleterious or protective alleles or environmental influences,
may be influencing the phenotype, and epigenetic or stochastic effects will
probably prove to be the most likely explanations.
It is predictable that the disorder would affect cones more than rods.
Immunohistochemical staining for GCAP-1 in human retinas has demonstrated
that there is intense staining of cone outer and inner segments, the cell
body from axon to pedicle, but weaker immunoreactivity in rod inner segments,
and very minimal immunostaining of rod outer segments.36-37
The GCAP-1 activates retinal guanylate cyclase (retGC-1), and has been
considered to restore levels of cyclic guanine monophosphate (cGMP) after
transduction38 (Figure 7). The GCAP-1 is inhibited by intracellular calcium, which
rises in the dark-adapted state.38-39
Studies have been undertaken to examine the function of the mutant and wild-type
protein by using a recombinant Y99C GCAP-1 mutant. The ability of the mutant
protein to activate retGC-1 in vitro at various calcium concentrations was
tested.40-41 The Y99C mutant GCAP-1
remained active even at calcium concentrations above 1 µmol/L and continued
to stimulate retGC-1. The Y99C GCAP-1 can activate retGC-1 even in the presence
of calcium-loaded wild-type GCAPs. Hence, the effect of this dominant negative
mutation is that the mutant protein has lost its calcium sensitivity, and
is effectively no longer a calcium switch. The mutant protein interferes with
the remaining wild-type GCAP, and the ability of GCAP-1 to be switched off
is lost, rendering it permanently active and retGC becomes constitutively
active within the physiologically relevant range of free calcium concentrations.
These experimental observations support the inference that the cone degeneration
associated with the Y99C mutation in GCAP-1 is a result of constitutive activation
of cGMP synthesis.
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Figure 7. Guanylate cyclase activator protein-1
(GCAP-1) stimulates retinal guanylate cyclase-1 (retGC-1), thus
augmenting conversion of guanosine triphosphate (GTP) to cyclic guanosine
monophosphate (cGMP) with consequent increase of the percentage of cGMP channels
that are open. Na+ indicates sodium; Ca2+, calcium.
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These results are consistent with a model in which enhanced retGC-1
activity in dark-adapted cones leads to elevated levels of cytoplasmic cGMP.
Evidence exists that continuously high levels of cGMP can cause photoreceptor
cell death.42 Retinal degeneration, with either
excess levels of cGMP, as in the case of mutations in phosphodiesterase  ,
or disease associated with insufficient cGMP, as in Leber congenital amaurosis,
exists.
It is difficult to predict what effect constant elevation of cGMP may
have on transduction kinetics, and the relationship between the phenotype
and the putative metabolic abnormality consequent on the mutation is not clear.
However, there is ample evidence that continuously high levels of cGMP may
cause photoreceptor cell death.42 The abnormalities
of the ON and OFF responses seen in family A may reflect abnormal transduction
kinetics. Alternatively, they may imply a posttransduction disturbance caused
by either abnormalities of the cones themselves and/or their synapses.43 There is no evidence to suggest consistent selective
involvement of either depolarizing (ON) or hyperpolarizing (OFF) pathways.
AUTHOR INFORMATION
Accepted for publication June 27, 2000.
Funded by grant 053405 from the Wellcome Trust, London, England, British
RP Society, Surrey, England, Medical Research Council, London, England, and
Foundation Fighting Blindness, Baltimore, Md.
We thank all the families participating in this study, and Seedevi Pieris,
MD, of Bedford Hospital, Bedford, England, for help in this study.
Corresponding author: Susan M. Downes, FRCOphth, Oxford Eye Hospital,
Woodstock Road, Oxford OX2 6HE, England (e-mail: susan.downes{at}ophthalmology.oxford.ac.uk).
From Moorfields Eye Hospital (Drs Downes, Holder, and Bird), and the
Institute of Ophthalmology (Drs Downes, Fitzke, Payne, Warren, Bhattacharya,
and Bird), London, England.
REFERENCES
| |
1. Small KW, Syrquin M, Mullen L, Gehrs K. Mapping of autosomal dominant cone degeneration to chromosome 17p. Am J Ophthalmol. 1996;121:13-18.
ISI
| PUBMED
2. Krill AE. Cone degenerations. In: Krill AE, Archer DB, eds. Krills Hereditary
Retinal and Choroidal Diseases, Vol 2: Hagerstown, Md: Harper &
Row; 1977:421-478.
3. Berson EL, Gouras P, Gurkel RD. Progressive cone degeneration, dominantly inherited. Arch Ophthalmol. 1968;80:77-83.
ISI
| PUBMED
4. Moore AT. Cone and cone-rod dystrophies. J Med Genet. 1992;29:289-290.
ISI
| PUBMED
5. Simunovic MP, Moore AT. The cone dystrophies. Eye. 1998;12:553-565.
ISI
| PUBMED
6. Daiger SP, Sullivan LS, Rossiter BJF. The RetNet: retinal information network. Available at: http://www.sph.uth.tmc.edu/RetNet/. Accessibility
verified September 14, 2000.
7. Nakazawa M, Kikawa E, Chida Y, Wada Y, Shiono T, Tamai M. Autosomal dominant cone-rod dystrophy associated with mutations in
codon 244 (Asn 211 His) and codon 184 (Tyr 184 Ser) of the peripherin/RDS
gene. Arch Ophthalmol. 1996;114:72-78.
ABSTRACT
8. Nakarawara M, Kikawa E, Chida Y, Tamai M. Asn244His mutation of the peripherin/RDS gene causing autosomal dominant
cone rod dystrophy. Hum Mol Genet. 1994;3:1195-1196.
FREE FULL TEXT
9. Jacobson SG, Kemp CM, Cideciyan A, et al. Spectrum of functional phenotypes in RDS mutations [abstract]. Invest Ophthalmol Vis Sci. 1994;35(suppl):S1044.
10. Fishman GA, Stone EM, Alexander KR, Gilbert LD, Derlacki DJ, Butler NS. Serine-27-phenylalanine mutation within the peripherin/RDS gene in
a family with cone dystrophy. Ophthalmology. 1997;104:299-306.
ISI
| PUBMED
11. Payne AM, Downes SM, Bessant DA, et al. 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;7:273-277.
FREE FULL TEXT
12. Kelsell RE, Gregory-Evans K, Payne AM, et al. Mutations in the retinal guanylate cyclase (RETGC-1) gene in dominant
cone-rod dystrophy. Hum Mol Genet. 1998;7:1179-1184.
FREE FULL TEXT
13. Freund CL, Gregory-Evans CY, Furukawa T, et al. Cone-rod dystrophy due to mutations in a novel photoreceptor-specific
homeobox gene (CRX) essential for the maintenance of the photoreceptor. Cell. 1997;91:543-553.
FULL TEXT
|
ISI
| PUBMED
14. Kelsell RE, Gregory-Evans GK, Gregory-Evans CY, et al. Localization of a gene (CORD7) for a dominant cone-rod dystrophy to
chromosome 6q. Am J Hum Genet. 1998;63:274-279.
FULL TEXT
|
ISI
| PUBMED
15. Online Mendelian Inheritance in Man (TM) Center for Medical Genetics Available at: http://www.ncbi.nlm.nih.gov/Omim. Accessibility
verified September 14, 2000.
16. Klystra JA, Aylsworth AS. Cone-rod retinal dystrophy in a patient with neurofibromatosis type
1. Can J Ophthalmol. 1993;28:79-80.
ISI
| PUBMED
17. Warburg M, Sjo O, Fledelius HC. Deletion mapping of a retinal cone-rod dystrophy: assignment to 18q21.1. Am J Med Genet. 1991;39:288-293.
FULL TEXT
|
ISI
| PUBMED
18. Tranebjaberg L, Sjo O, Warburg M. Retinal cone dysfunction and mental retardation associated with a de
novo balanced translocation 1;6 (q44;q27). Ophthalmic Paediatr Genet. 1986;7:167-173.
ISI
| PUBMED
19. Payne AM, Downes SM, Bessant DA, Bird AC, Bhattacharya SS. Founder effect in 172 mutation. Am J Hum Genet. 1998;62:192-195.
FULL TEXT
|
ISI
| PUBMED
20. Marmor MF, Zrenner E. Standard for clinical electroretinography (1994 update). Doc Ophthalmol. 1995;89:199-210.
FULL TEXT
|
ISI
| PUBMED
21. Marmor MF, Holder GE, Porciatti V, Trick GL, Zrenner E. Guidelines for basic pattern electroretinography: recommendations by the
International Society for Clinical Electrophysiology of Vision. Doc Ophthalmol. 1995-96;91:291-298.
22. Marmor MF, Zrenner E for the International Society for Clinical Electrophysiology of Vision. Standard for clinical electro-oculography. Arch Ophthalmol. 1993;111:601-604.
ABSTRACT
23. Jacobson SG, Voigt WJ, Parel JM, et al. Automated light- and dark-adapted perimetry for evaluating retinitis
pigmentosa. Ophthalmology. 1986;93:1604-1611.
ISI
| PUBMED
24. Steinmetz RL, Haimovici R, Jubb C, Fitzke FW, Bird AC. Symptomatic abnormalities of dark adaptation in patients with age-related
Bruch's membrane change. Br J Ophthalmol. 1993;77:549-554.
FREE FULL TEXT
25. Alexander KR, Fishman GA. Prolonged rod dark adaptation in retinitis pigmentosa. Br J Ophthalmol. 1984;68:561-569.
FREE FULL TEXT
26. Chen JC, Fitzke FW, Pauleikhoff D, Bird AC. Functional loss in age-related Bruch's membrane defect with choroidal
perfusion defect. Invest Ophthalmol Vis Sci. 1992;33:334-340.
FREE FULL TEXT
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