Disease Expression in Usher Syndrome Caused by
VLGR1 Gene Mutation (USH2C) and Comparison with
Sharon B. Schwartz,1Tomas S. Aleman,1Artur V. Cideciyan,1Elizabeth A. M. Windsor,1
Alexander Sumaroka,1Alejandro J. Roman,1Tej Rane,1Elaine E. Smilko,1Jean Bennett,1
Edwin M. Stone,2William J. Kimberling,3Xue-Zhong Liu,4and Samuel G. Jacobson1
PURPOSE. To investigate the retinal disease expression in
USH2C, the subtype of Usher syndrome type 2 recently shown
to be caused by mutation in the VLGR1 gene, and compare
results with those from USH2A, a more common cause of
METHODS. Three siblings with USH2C and 14 patients with
USH2A were studied. Visual function was measured by kinetic
perimetry, static chromatic perimetry, and electroretinography
(ERG). Central retinal microstructure was studied with optical
coherence tomography (OCT).
RESULTS. The siblings with VLGR1 mutation showed abnormal
photoreceptor-mediated function in all retinal regions, and
there was greater rod than cone dysfunction. USH2A had a
wider spectrum of disease expression and included patients
with normal function in some retinal regions. When abnormal-
ities were detected, there was more rod than cone dysfunction.
Retinal microstructure in both USH2C and USH2A shared the
abnormality of loss of outer nuclear layer thickness. Central
retinal structure in both genotypes was complicated by cystic
macular lesions. A coincidental finding in an USH2C patient
was that oral intake of antihistamines was associated with
temporary resolution of the macular cystic change.
CONCLUSIONS. USH2C and USH2A manifest photoreceptor dis-
ease with rod- and cone-mediated visual losses and thinning of
the outer nuclear layer. An orderly progression through disease
stages was estimated from cross-sectional and limited longitu-
dinal data. Intrafamilial and interfamilial variation in retinal
severity in USH2A, however, suggests that genetic or nonge-
netic modifiers may be involved in the disease expression.
(Invest Ophthalmol Vis Sci. 2005;46:734–743) DOI:10.1167/
loss. Three subtypes are clinically distinguishable, mainly by
degree of hearing dysfunction and the presence or absence of
vestibular abnormality (reviewed in Refs. 1–3). In patients with
USH type II (USH2), the most common subtype,4,5the congen-
ital hearing loss is relatively mild at low frequencies and severe
at high frequencies and can be either stable or progressive.6,7
Patients with USH2 do not have vestibular dysfunction, in
contrast to the profound hearing loss with vestibular abnor-
mality in USH1. USH3 has progressive hearing loss with vari-
able vestibular abnormalities.8
Approximately 70% of USH2 is caused by mutations in
USH2A (MIM 608400) on 1q41,3,9but molecular heterogeneity
has been demonstrated.10–13A genome scan in 12 USH2 fam-
ilies who were unlinked to 1q41 and USH2B (MIM 276905)
markers localized a third USH2 gene to the long arm of chro-
mosome 5.14More recently, the USH2C-associated gene at this
locus was identified to be very large G protein-coupled recep-
tor-1 (VLGR1; MIM 605472).15
Details of retinal phenotype in USH2C have not been de-
scribed. We report results of psychophysical, electrophysiolog-
ical, and retinal imaging studies in affected members of a family
with USH2C10,14and draw comparisons by using similar anal-
yses in a group of patients with USH2A mutations.
sher syndrome (USH) is an autosomal recessive group of
diseases characterized by retinal degeneration and hearing
MATERIALS AND METHODS
Patients with USH, representing 11 families, underwent clinical ocular
examinations and visual function studies. Molecular results for the
USH2C family are published (family 1848 in Refs. 14,15). Other pa-
tients with USH2A were identified.13All subjects gave informed con-
sent, institutional review board approval was obtained, and the tenets
of the Declaration of Helsinki were followed.
Visual Function Studies
Psychophysics. Kinetic perimetry was performed with two
targets (V-4e and I-4e). Dark- and light-adapted threshold chromatic
perimetry was performed with a modified automated perimeter to
determine rod and L/M (long/middle wavelength) cone function. Tech-
niques, methods of data analysis, and normal results have been de-
Electroretinography. Full field electroretinograms (ERGs)
were performed with a standard protocol. Details of the methods and
normal data have been published.17–19
Optical Coherence Tomography. Cross-sectional images of
the central retina were obtained with commercially available optical
From the1Department of Ophthalmology, Scheie Eye Institute,
University of Pennsylvania, Philadelphia, Pennsylvania; the
ment of Ophthalmology, Howard Hughes Medical Institute, University
of Iowa Hospitals and Clinics, Iowa City, Iowa; the3Usher Syndrome
Center, Boys Town National Research Hospital, Omaha, Nebraska; and
the4Department of Otolaryngology, University of Miami, Miami, Flor-
Supported by National Eye Institute Grants EY13385 and
EY13729; the Foundation Fighting Blindness; Macula Vision Research
Foundation; Macular Disease Foundation; Research to Prevent Blind-
ness; the Mackall Trust; and the F. M. Kirby Foundation.
Submitted for publication September 23, 2004; revised November
11, 2004; accepted November 12, 2004.
Disclosure: S.B. Schwartz, None; T.S. Aleman, None; A.V. Ci-
deciyan, None; E.A.M. Windsor, None; A. Sumaroka, None; A.J.
Roman, None; T. Rane, None; E.E. Smilko, None; J. Bennett, None;
E.M. Stone, None; W.J. Kimberling, None; X.-Z. Liu, None; S.G.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be marked “advertise-
ment” in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Corresponding author: Samuel G. Jacobson, Scheie Eye Institute,
University of Pennsylvania, 51 North 39th Street, Philadelphia, PA
Investigative Ophthalmology & Visual Science, February 2005, Vol. 46, No. 2
Copyright © Association for Research in Vision and Ophthalmology
coherence tomography (OCT) instruments (OCT1 and OCT3; Carl
Zeiss Meditec, Dublin, CA), according to described methods.18,20,21
Scans were 4.5 mm long. Each scan, formed by a series of longitudinal
reflectivity profiles (LRPs), was analyzed with custom-developed com-
puter programs.18,21–24Retinal thickness measurements were made at
the fovea and at a perifoveal temporal retinal locus. Outer nuclear layer
thickness was quantified at the perifoveal locus. These measurements
were based on the distance between previously defined features on
Phenotype of USH2C
The USH2C family (Table 1, family 1) had four affected siblings
(Fig. 1A). The causative compound heterozygous mutations in
VLGR1 have been identified as Q2301X (6901C3T) and
I2906FS (8716insAACA).15Table 1 gives clinical characteristics
of three affected family members at their first visit. Audiomet-
ric evaluations available in the siblings (P1 at age 42 years, P5
at age 39, and P6 at age 20) showed bilateral hearing impair-
ment with a downsloping configuration: there was moderate-
to-severe loss at low frequencies and severe-to-profound loss at
Retinal Dysfunction. P6, P5, and P1 (at ages 27, 33, and
40 years, respectively) showed a similar pattern of retinal
dysfunction by ERG (Fig. 1B). There were no detectable rod
b-waves to a dim blue flash of light in the dark-adapted state.
The maximal response to a white flash of light, dark-adapted,
had reduced a- and b-wave amplitudes. Cone ERGs (to 1- or
29-Hz stimuli) were reduced in amplitude and delayed in tim-
ing. Rod and cone perimetry was performed at the same ages.
Dark-adapted perimetry, displayed as maps of rod sensitivity
loss, showed that P6 retained a central island of rod-mediated
function. Light-adapted perimetry, displayed as a map of L/M
cone sensitivity loss, showed the central island and a small
temporal–inferior peripheral region of detectable function. P5
and P1, at older ages than P6, had more peripheral function.
Shared by all patients was an extensive midperipheral region
with no detectable rod- or L/M cone-mediated function (Fig.
Kinetic perimetry also illustrates the different extents of
peripheral function in the siblings (Fig. 2; Table 1). P6, the
youngest sibling, had a central island but no detection of the
stimuli beyond the 20° isopter (Fig. 2A). Both older siblings
showed midperipheral absolute scotomas and detectable pe-
ripheral function (Figs. 2B, 2C). The kinetic visual field change
over a 7-year interval in P1 (ages 40–47 years) is also shown
TABLE 1. Clinical Characteristics of the USH2C and USH2A Patients
Age at First Visit
Family 1 (6901C3T/8716insAACA)
Family 2 (2299delG/2299delG)
Family 3 (2299delG)
Family 4 (2299delG/1214delA)
Family 5 (2299delG)
Family 6 (2299delG/921insCAGC)
Family 7 (1550G3C/1550G3C)
Family 8 (2299delG)
Family 9 (2299delG)
Family 10 (2299delG)
Family 11 (1679delC)
?0.5089/?1 ND9 Delay
?1.5015/?1 NDND ND
?1.0094/?1 ND7 Delay
?1/?1 np npnp
?0.5061/?1 NDND ND
?4.00 75/?1 NDND ND
N, normal; np, not performed; ND, not detectable.
* Best corrected visual acuity; similar in the two eyes unless specified.
† Spherical equivalent; average of both eyes.
‡ Average of both eyes, expressed as a percentage of normal mean for V-4e or I-4e target; 2 SD below mean equals 90%.17
§ Expressed as percent of mean normal amplitude, if ?2 SD of normal.19
? One allele identified only in some families.
IOVS, February 2005, Vol. 46, No. 2
Usher Syndrome 2C and 2A735
(Fig. 2C). The midperipheral scotomas evolved to a complete
annular midperipheral defect that separated the central from
the far peripheral islands.
Whereas severity of peripheral dysfunction appeared unre-
lated to age in this family, central rod- and cone-mediated
function was more abnormal in the older siblings (Fig. 2D). P6,
at age 27, retained the greatest central extent and degree of
rod-mediated function. Rod sensitivity loss over most of the
central island was approximately 15 to 20 dB, but there was a
decline to no measurable rod function at eccentricities greater
than 24°. Cone sensitivity loss in the central island of P6 (not
shown) was between 5 and 10 dB at most loci, declining to
unmeasurable function at 22° to 24° from fixation. P5 (age 33)
and P1 (age 40) also had detectable but impaired central
rod-mediated function that extended only to approximately
12° from fixation (Fig. 2D). P5 had a minimum of 15 to 20 dB
rod sensitivity loss; cone sensitivity loss was approximately 5 to
10 dB. P1 had several paracentral loci with rod-mediated stim-
ulus detection that were at least 15 dB reduced in sensitivity.
Most other loci were cone-mediated with sensitivity losses of 5
to 10 dB.
Central Retinal Micropathology. A normal cross-sec-
tional image along the horizontal meridian of the central retina
(Fig. 3A) shows a foveal depression and definable laminae.
Overlaid LRPs at the fovea and at a temporal perifoveal retinal
locus (5.6° or 1.7 mm) highlight the differences between
retinal lamination at the two locations. At the foveal locus,
there was a reflection from the vitreoretinal interface, a decline
in reflectivity representing the nuclear layer of cone photore-
ceptors, and a multipeaked high reflectivity deep in the retina,
named the outer retinal–choroidal complex (ORCC).22,23,25
The ORCC represents photoreceptor inner segments (IS) and
outer segments (OS), the retinal pigment epithelium (RPE), and
the anterior choroid.20,21At the temporal perifoveal locus, a
region of high rod density,26there is a reflection at the vitreo-
retinal interface—deeper high and low reflectivities, represent-
ing synaptic and cellular layers and the ORCC (Fig. 3A).
Cross-sectional central retinal imaging through fixation
from 7.5° nasal to 7.5° temporal was performed on the siblings
with USH2C mutation. Scans are shown for both eyes of P6 and
P5 at a single visit and P1 at two different ages (Figs. 3B–D).
Details of the retinal laminar architecture are illustrated with
LRPs overlaid at the fovea and at the temporal perifoveal locus.
The scans of P6 at age 30 showed interocular asymmetry of
central structure (Fig. 3B). The fovea of the right eye appeared
normal but had slightly increased thickness (188 ?m; normal
mean ? SD, 142.5 ? 14.2 ?m, n ? 8). The ORCC was
multipeaked similar to the normal waveform. Visual acuity was
20/25. At the temporal locus, outer nuclear layer (ONL) thick-
ness was reduced (32 ?m; normal mean ? SD, 62.9 ? 5.1 ?m,
n ? 8). Overall retinal thickness at this locus was at the upper
limits of normal (268 ?m; normal mean ? SD, 243.5 ? 10.8
?m, n ? 8), suggesting increased inner retinal thickness. The
left eye of P6, in contrast, showed a dramatically increased
foveal thickness of 472 ?m with cystic changes.27,28The
ORCC was multipeaked, and visual acuity was 20/30. At the
temporal locus, the retina was also thickened (372 ?m): The
ONL was reduced to 32 ?m but the INL was greatly expanded.
P5 at age 36 years, for comparison, had very little interocu-
lar asymmetry in microstructure (Fig. 3C). The right eye
showed no major distortion of foveal architecture, but there
was a slight increase in thickness (178 ?m). The left eye had
Circles: females; squares: males; filled symbols: affected individuals;
open symbols: unaffected individuals. (B) Rod, mixed cone–rod, and
cone ERGs from three siblings are compared with ERGs of a normal
subject (age 35 years). Calibrations (vertical, microvolts; horizontal,
milliseconds) are to the right and below the waveforms. (C) Static
threshold perimetry results, dark-adapted (top) and light-adapted (bot-
tom), are displayed as grayscale maps of rod and cone sensitivity loss.
Scale has 16 levels of gray, representing 0- to 30-dB losses. The
physiological blind spot is represented as a black square at 12° in the
temporal field. N, nasal; T, temporal; I, inferior; S, superior visual field.
Rod and cone function in an USH2C family. (A) Pedigree.
progression in USH2C. (A–C) Kinetic
perimetry in P6 and P5 and in P1 at
two different ages representing a
7-year interval. (D) Dark-adapted sen-
sitivity profiles with a 500-nm stimu-
lus across the central 60° of retina in
the three affected members of family
1 and normal subjects (gray, mean ?
2 SD; n ? 21, ages 15–42 years).
Hatched area: physiological blind
spot region. N, nasal; T, temporal vi-
Visual field patterns and
736Schwartz et al.
IOVS, February 2005, Vol. 46, No. 2
less of a foveal depression and slightly greater thickness (216
?m). At the temporal loci in both eyes, ONL thickness was
reduced (26 ?m), and the ORCC was single peaked, a feature
associated with loss of IS/OS in retinal degenerations.22,23
Serial scans in P1, separated by 2 years, show a progression
to interocular asymmetry and cystic changes in the right eye
(Fig. 3D). At age 40 years, foveal thickness of the right eye was
normal (152 ?m), but it had increased to 380 ?m at age 42. The
foveal ORCC was multipeaked on both visits; visual acuities
were 20/20 at age 40 and 20/25 at age 42. The temporal retinal
locus of the right eye was similar on the two visits with
reduced ONL (24 ?m). The ORCC at age 40 retained an early
component attributable to the IS/OS, but at age 42 it was single
peaked. Foveal thickness of the left eye was 146 and 144 ?m
at the two ages. Visual acuities were 20/20 and 20/25. The
temporal retinal locus of the left eye differed on the two visits.
The multipeaked ORCC at age 40 changed to a single-peaked
ORCC at age 42, and at both times, the ONL was reduced (26
and 30 ?m, respectively).
Serial scans from the left eye of P6 over a 7.5-year period
(Fig. 3E) showed an unexpected result. At age 27, visual acu-
ities were 20/20 and 20/30 in right and left eyes, respectively,
and there were prominent cystic changes only in the left eye
that did not change remarkably over 4.5 years (time 0 to 4.5
years; time 3 years is age 30 years; Fig. 3B). The patient was
taking no prescription medicines during this interval. At the
age of 32 (time ?4.6 years; Fig. 3E), the patient had seasonal
allergic symptoms and began taking the antihistamine cetiri-
zine (recalled dose, 10 mg/d), which was continued for ap-
proximately 3 months. Generalized pruritus and dermatogra-
phism of unknown cause occurred, and three further antihis-
tamines were added in an attempt by the patient, with medical
guidance, to relieve the symptoms: fexofenadine at 180 mg/d,
hydroxyzine at 100 mg/d in divided doses, and diphenhydra-
mine ad libitum (25 mg). The four antihistamines were taken
together for 1 month, after which time cetirizine and diphen-
hydramine were discontinued. For two more months, hy-
droxyzine and fexofenadine were continued, and the pruritus
disappeared. While taking these last two medications, the pa-
tient returned for follow-up examination (elapsed time, 5
years) and reported the events of the previous few months. No
visual change was noted by the patient, and visual acuities
remained similar to those recorded previously. The prominent
and previously persistent macular cystic changes of the left eye
were no longer detectable. Hydroxyzine and fexofenadine
were continued by the patient for a further month and then
stopped. On a visit 4 months after cessation of all antihista-
mines (5.5 years), the cystic maculopathy was again evident
and similar to that of previous visits. Subsequent examinations
have shown no dramatic changes in this eye (times, 6.0 and 7.5
years; Fig. 3E).
Phenotype of USH2A
Table 1 gives clinical characteristics of 14 patients in 10 fami-
lies with USH2A gene mutations. Audiometric evaluations
were available from 10 patients and all showed bilateral hear-
ing impairment with a downsloping configuration.
Retinal Dysfunction. For comparison with results of ERG
and chromatic perimetry in USH2C family 1 (Fig. 1), similar
studies are shown from three affected siblings in USH2A family
2 (Fig. 4). P4, at age 17, had ERG results (Fig. 4B) that were at
the lower limit of normal.19Rod and cone sensitivities were
normal or nearly normal in a wide extent of the central and
midperipheral visual field, but there was a decline in sensitivity
in the temporal field (Fig. 4C). P5 (dizygotic twin of P4), also
at age 17, had pronounced abnormalities in ERGs and perime-
try. Rod ERG b-waves were not detectable and the mixed
cone–rod ERG a- and b-wave amplitudes were reduced. Cone
ERGs to 1-Hz stimuli were within normal limits for amplitude.
The 29-Hz response had two components that were both
structure in USH2C. (A–D) Cross-sec-
tional retinal images obtained with
OCT from the central 15° of the right
eye of a 27-year-old normal subject
(inset: scan location on fundus draw-
ing) and both eyes of P6 (age 30), P5
(age 36), and P1 (ages 40 and 42).
Images are displayed with the loga-
rithm of reflectivity mapped to a
grayscale. LRPs, averaged from 1°
sections, are superimposed on the
images at (or near, so as not to ob-
tions: the fovea and at 5.6° (1.7 mm)
in the temporal retina. F, fovea; N,
nasal; T, temporal retina; INL, inner
nuclear layer; OPL, outer plexiform
layer; ONL, outer nuclear layer; IS/
OS, photoreceptor inner/outer seg-
ments; RPE, retinal pigment epithe-
lium. (E) Serial cross-sectional retinal
images in P6 (left eye) over a 7.5-year
interval. Hatched bar along the time
axis indicates the period of oral anti-
IOVS, February 2005, Vol. 46, No. 2
Usher Syndrome 2C and 2A737
reduced in amplitude (Fig. 4B). Rod sensitivities were reduced
across most of the visual field outside the center (Fig. 4C).
Cone sensitivities were less affected than those of the rods. P1,
nearly a decade older than his siblings, had a nondetectable
ERG and only a central island with impaired cone-mediated
function (Figs. 4B, 4C).
Kinetic perimetry in family 2 (Fig. 5A) also showed different
degrees of visual loss in the twins at age 17 years. P4 and P5
both had a normal extent of peripheral field with the V-4e test
target. With the smaller target (I-4e), P4 had a reduced extent
of temporal field, but P5 showed a more generalized reduction
to a central island of 25° to 30° in diameter. Serial results over
a 5-year interval in P5 and the results in P1, the older sibling,
suggest a pattern of kinetic field progression. P5, from ages 17
to 22 years, lost substantial peripheral and paracentral field.
ERG parameters over this interval (not shown) also supported
a dramatic reduction in function. The mixed response lost
approximately 50% amplitude and cone ERGs lost 60% to 80%
amplitude. P1, at age 26 years, was limited to a small central
Central rod-mediated function in P4 at age 17 was at the
lower limit of normal (Fig. 5B, top panel); cone sensitivity (not
shown) was normal. P1 at age 26, representing a more severe
disease expression, had a small central island with no measur-
able rod function and reduced cone sensitivity (Fig. 5B, top
panel). Intermediate disease severities were suggested in the
results of P5 separated by a 5-year interval (Fig. 5B, lower
panel). Rod sensitivity at age 17 was nearly normal centrally
but was reduced by ?15 dB at eccentricities beyond 10° to
15°. At age 22 years, rod sensitivity was abnormally reduced at
paracentral loci by 10 to 15 dB and declined to 30 dB rod
sensitivity loss at eccentricities beyond 15°. Cone function was
within normal limits in the central 20° on both visits. A decline
in sensitivity with eccentricity was present at age 17 and was
more exaggerated at age 22 (data not shown).
The patterns of results of kinetic perimetry in four repre-
sentative USH2A patients from different families (Fig. 5C) illus-
trate a range of disease expression. Family 7, P2 (age 29 years),
for example, retained full peripheral field extent with the V-4e
target but was limited to a central island with the I-4e target.
This degree of disease was greater than that in family 2, P4 and
P5, at age 17. Family 10, P1 (age 38) showed midperipheral
absolute scotomas and family 4, P1 (age 29) had a complete
annular midperipheral scotoma separating central from periph-
eral islands. Serial results over 14 years in family 5, P1 docu-
mented the progression from relative to absolute midperiph-
eral scotomas (Fig. 5E).
Central rod function measurements in three USH2A pa-
tients from different families (Fig. 5D) suggest a disease se-
quence from reduced (by 10–15 dB) but measurable rod sen-
sitivity in the central 20° to 30° (family 3, P1), to a more limited
extent (?20°) of increasingly impaired rod function (family 10,
P1), to a small central cone-mediated island with no detectable
rod function (family 6, P1). This proposed sequence from
cross-sectional data resembles the serial dark-adapted profiles
over a 14-year interval in family 5, P1 (Fig. 5F). From a nearly
40° extent of rod-mediated function with normal central rod
sensitivities at age 36, there was progression to a cone-medi-
ated central island of ?20° by age 50. During this interval, cone
sensitivity remained within normal limits in the very central
field, but the horizontal extent of measurable function declined
(data not shown).
Central Retinal Micropathology. Cross-sectional retinal
imaging of the central retina was performed in seven patients
with USH2A mutations. In family 2, the siblings P4 and P1
exemplified different degrees of abnormality in central retinal
architecture (Fig. 6A). The right eye of P4 at age 17 years had
a normal-appearing fovea with a thickness of 150 ?m; ORCC
was multi-peaked and visual acuity was 20/20. The perifoveal
temporal locus was also nearly normal except for an ONL
thickness of 46 ?m, which was slightly reduced. The right eye
of P1 at age 27 years showed an increased foveal thickness of
428 ?m with a pattern of macular edema. The ORCC was
multi-peaked and visual acuity was 20/25. The temporal retinal
locus had discernible laminae but retinal thickness was re-
duced (208 ?m). The ONL thickness was thinned to 16 ?m,
and the ORCC was single-peaked.
Serial scans in P5, separated by 3 to 4 years, illustrate a
progression to overt cystic macular change in the left eye
during this interval (Fig. 6B). The right eye of P5 at ages 17 and
21 had normal-appearing foveal architecture with a multi-
peaked ORCC; thickness in each eye was slightly increased
(188 ?m at 17, and 194 ?m at 22 years). Visual acuity was
20/20 at ages 17 and 21. Perifoveal temporal loci showed a
normal overall retinal thickness at both ages (248 and 254 ?m,
respectively) but ONL thickness was reduced (20–22 ?m),
suggesting an increase in inner retinal thickness. The left eye
fovea of P5 at age 18 had slightly greater thickness at 200 ?m,
and at age 21 the fovea was greatly thickened at 360 ?m with
obvious cystic change. The ORCC at both ages was multi-
peaked, and visual acuity was 20/20 at age 18 and 20/25 at age
21. Perifoveal temporal loci were not remarkably different
between visits. Overall retinal thickness was within normal
limits at both ages (266 and 264 ?m, respectively), but ONL
thickness was reduced (22–24 ?m) with a single-peaked
ORCC; again, this suggests an increase in inner retinal thick-
Two further examples of interocular asymmetry and micro-
pathology related to cystic maculopathy and retinal degenera-
tion in USH2A patients are shown (Figs. 6C, 6D). P1 of family
3 at age 18 years had 20/20 visual acuity in both eyes. The right
eye had cystic changes and a greatly increased foveal thickness
of 438 ?m, whereas the left eye’s foveal thickness was in-
Symbols as in Figure 1. (B) Rod, mixed cone–rod, and cone ERGs from
three siblings are compared with ERGs of a normal subject. (C) Static
threshold perimetry results in the dark-adapted (top) and light-adapted
(bottom) states are displayed as grayscale maps of rod and cone
sensitivity loss. Scale has 16 levels of gray, representing 0- to 30-dB
losses. N, nasal; T, temporal; I, inferior; S, superior visual fields.
Rod and cone function in an USH2A family. (A) Pedigree.
738Schwartz et al.
IOVS, February 2005, Vol. 46, No. 2
creased but far less so at 236 ?m. The ORCC was multi-peaked
in both eyes. At the perifoveal temporal loci, overall retinal
thickness was slightly increased (280 ?m). The ONL was re-
duced in the right eye (14 ?m) more than in the left eye (24
?m), with both showing a single-peaked ORCC, and the inner
retina was thickened. P1 of family 4 had visual acuity of 20/25
in each eye and each eye retained a multi-peaked ORCC. The
right eye foveal thickness was increased at 266 ?m, and there
were cystic macular changes with an apparent operculum
suggesting an evolving macular hole. Foveal thickness in the
left eye was far greater at 420 ?m with cystic spaces. Perifoveal
temporal loci had generally thinned retina in both eyes (144
and 164 ?m, respectively), a reduced ONL to 16 to 18 ?m with
single-peaked ORCC and thinned inner retinal LRP compo-
In two further patients (not shown), family 9, P1 and family
5, P1 (Table 1), both with visual acuity of 20/25 or better,
cross-sectional images showed normal foveal architecture and
thickness, but there was thinned retina at the perifoveal tem-
poral locus with reduced ONL.
The Mutant Genes Causing USH2C and USH2A
Gene and mutation discoveries have defined the USH2C and
USH2A disease subtypes, but the roles of the gene products in
the retina are not completely understood. VLGR1 (or
MASS1),29the USH2C gene, encodes a member of the G
protein–coupled receptor (GPCR) family of proteins (reviewed
in Ref. 30). VLGR1 is the largest cell surface protein known and
has similarities to family B GPCRs, specifically a subgroup of
large N-terminal seven-transmembrane receptors.31The extra-
cellular portion of the VLGR1 protein contains repeated units
resembling calcium-exchanger ? (calx-?) motifs, which distin-
guishes it from other GPCRs.31,32Both of the VLGR1 mutations
causing USH2C in family 1 of this study occur in a calx-?
motif.15VLGR1 also contains a pentraxin motif31that is similar
to the LamG domain of the USH2A protein.33
Clues to the function of the molecule come from murine
studies of VLGR1 transcript expression, which is highest in the
progression in USH2A. (A) Kinetic
perimetry results in family 2, P4 and
P1, and in P5 at two different ages
representing a 5-year interval. (B)
Dark-adapted sensitivity profiles in
the three affected members of family
2 and normal subjects (gray, mean ?
2 SD; as in Fig. 2). Normal data
(mean ? 2 SD; n ? 5, ages 26–54
years) for this stimulus on a cone
plateau is displayed for comparison
with patient profiles that are cone
mediated (open symbols). (C) Ki-
netic perimetry of patients with dif-
ferent degrees of visual loss. (D)
Dark-adapted sensitivity profiles of
representative patients. (E) Kinetic
perimetry in family 5, P1 at two dif-
ferent ages, representing a 14-year
interval. (F) Dark-adapted sensitivity
profiles of family 5, P1 at four differ-
ent ages during the 14-year interval.
N, nasal; T, temporal visual fields; F,
Visual field patterns and
IOVS, February 2005, Vol. 46, No. 2
Usher Syndrome 2C and 2A739
embryonic central nervous system. VLGR1 transcripts are ex-
pressed by neural retinal precursors and by cells destined to
become retinal pigment epithelium.34The suggestion has thus
been made that mutations in VLGR1 may affect neural devel-
opment.34,35VLGR1 expression continues at low levels in
adulthood,32,34implying an additional role in maintenance.34
The USH2A product usherin is thought to be either a cell
adhesion molecule or an extracellular matrix protein, based on
the presence of laminin and fibronectin domains.36,37USH2A
mRNA expression was originally found to be limited mainly to
the retina and cochlea, and cellular expression in rodent and
human retina was in the outer nuclear layer.38Usherin has also
been reported to be widely expressed in the basement mem-
branes of several other rodent and human tissues.39,40Usherin
is stabilized in basement membranes through its interaction
with type IV collagen.41In contrast to the high fetal expression
of VLGR1 transcripts, USH2A transcripts are expressed at high-
est levels in the adult neural retina,42possibly because the
protein functions in cellular homeostasis.38
USH2C and USH2A Retinal Phenotypes
The retinal degenerative component of all Usher syndromes
remains incurable. If gene-based interventions for the retina are
in the future for patients with USH, the pathogenesis of the
retinopathies must be clarified. Naturally occurring or geneti-
cally engineered murine or other models of human dis-
eases43,44have become key to the analysis of pathobiology.
None of the USH models, however, has a pronounced retinal
degenerative component to the phenotype.2Understanding
the human retinal phenotype is not only a prerequisite for any
proposed intervention and for eventual comparison with ani-
mal models, but also (and specifically in the case of USH) this
information can help bridge the wide gap between gene dis-
covery and disease expression.
USH2C has not previously been studied in detail for retinal
phenotype. The three siblings with USH2C showed severe
peripheral rod and cone dysfunction when first examined in
the third and fourth decade of life (within a few years of the
first retinal diagnosis).15There were no retinal regions with
normal rod function, but there were islands of impaired rod
function. Rod and cone ERG findings mirrored rod and cone
psychophysics. Photoreceptors appear to progress to degener-
ation in a pattern of rod worse than cone and peripheral worse
than central retina. Central retinal architecture can appear
normal except when distorted by macular cystic changes. At
the perifoveal locus, the outer nuclear layer was reduced in all
The USH2A phenotype showed many similarities to USH2C
and one notable difference. Some USH2A patients had normal
rod and cone function and nearly normal outer nuclear layer
thickness (at the locus measured). Studying further USH2C
patients may make this difference disappear. Among the simi-
larities to USH2C, all regions showing retinal dysfunction by
chromatic perimetry had greater rod than cone losses, and the
retina-wide ERG measures were again concordant. As in
USH2C, the photoreceptor dysfunction in USH2A patients ap-
peared to progress to degeneration in a peripheral worse than
central pattern. Central retinal structure by OCT was compli-
cated by cystic changes in four of seven patients studied. An
USH2A disease sequence, based on cross-sectional data and
limited longitudinal data, would be as follows: patients could
have normal or nearly normal rod and cone function (and
structure) in large expanses of retina that progressed at differ-
ent rates to impaired rod and less impaired cone function, to
total loss of rod function and retained, albeit severely reduced,
How do the present results compare with earlier retinal
studies of molecularly-defined USH2A patients? We are aware
of only two studies.45,46In one study of 37 USH2A patients,45
ERGs were reported as not detectable in 35 (age range, 20–59
years) of 37. Two patients (monozygotic twins at age 13) were
described as having subnormal rod and cone function. Kinetic
perimetry results were listed as ring scotomas and residual
central islands. Visual acuity declined with age, and fundus-
copic hallmarks of retinal degeneration (attenuated vessels and
pigmentary retinopathy) increased with age. Another recent
work compared USH2A with USH1B patients by using scores
of functional vision.46Results of certain studies of ungeno-
typed USH2 patients are worthy of mention in relation to the
present results. The kinetic fields in our patients resembled
those illustrated in an earlier study of visual field progression in
tional retinal images obtained with OCT from the central 15° of the
right eye of family 2, P4 (age 17 years), P1 (age 27), and both eyes of
P5 at different ages (ages 17, 18, and 21 years), representing about a
4-year interval. (C) Cross-sectional retinal images from both eyes of
family 3, P1. (D) Cross-sectional retinal images from both eyes of family
4, P1. Images are displayed with the logarithm of reflectivity mapped
to a grayscale. LRPs, averaged from 1° sections, are superimposed on
the images as in Figure 3. N, nasal; T, temporal retina; F, fovea.
Central retinal microstructure in USH2A. (A–B) Cross-sec-
740 Schwartz et al.
IOVS, February 2005, Vol. 46, No. 2
retinal degenerations that included USH2 patients (pattern III,
10/24 USH2 patients).47Data reduction in other studies of
kinetic perimetry in USH2 prevents comparison.48,49Previous
histopathologic studies of USH2 patients showed many of the
features observed in our noninvasive studies of USH2C and
USH2A; foveal macular cystic change, retained perifoveal lam-
inar architecture but reduced outer nuclear layer thickness; the
presence of rods and cones, but shortened outer segments in
the more central retina; and residual cones but no rods in more
In the recent USH literature, the term phenotypic variability
is mentioned in different contexts. Certain genes found to
cause USH1 also cause nonsyndromic deafness (reviewed in
Ref. 2). USH2A mutation has been associated with nonsyn-
dromic RP.52–55Concerning the USH2A retinal disease spec-
trum, there is a single report of monozygotic twins with re-
ported differences in visual deficit (as well as differences in
hearing and vestibular function). It was suggested that disease
severity may not be entirely determined by the USH2A gene
mutation but may be complicated by other factors.56We found
major differences in retinal disease severity at the age of 17
years in the dizygotic twins of family 2 and this would add
further support to the contention that there may be important
roles for modifier genes and environmental factors in USH2A.
Although the different severities of retinal disease expression
in patients in the present study are interpretable as stages of
progression, there was no clear relationship between severity
and age. Trying to understand how much of this retinal phe-
notypic variation is due to the specific USH2A mutation and
how much to other factors, and which factors, may be useful
in the development of therapeutic strategies for this very com-
mon form of USH and autosomal recessive RP.55
Macular Cystic Lesions in USH2C and USH2A
Foveal lesions, and specifically cystoid macular edema, are a
well-known feature not only of USH but of nonsyndromic
retinitis pigmentosa (RP; for example, Refs. 57–59). The inci-
dence of macular edema in RP has been most commonly
reported to be between 3% and 20% (for example, Refs.
27,57,60–62). In USH2, it has been estimated that approxi-
mately 8% of patients have macular edema; greater percentages
have been noted in USH1 patients.58,63In the USH2C and
USH2A patients, we studied with OCT, there were cystic
macular abnormalities in 6 of 10 patients. Serial data docu-
mented progression to macular cystic change over a period of
years in a patient from each molecular subtype. Although the
OCT features of cystic maculopathy in many different retinop-
athies have been well-documented (for example, Ref. 64),
there are very few reports of OCT in patients with RP27,28,64
and no reports in USH.
USH2C and USH2A patients had the expected OCT findings
of major increases in foveal thickness in some eyes, but there
could also be more subtle changes. Of interest, the latter
occurred in the contralateral eyes of those with large hypore-
flective lesions (for example, family 1, P6, RE; family 2, P5, RE;
and family 3, P1, LE) suggesting the macular changes were a
bilateral process with asymmetry. Serial data showed that there
could be relatively small degrees of foveal thickening that
anticipated overt macular cystic change by years (for example,
family 2, P5, LE). The horizontal extent of the abnormality was
detectable at the perifoveal temporal locus in some eyes with
foveal thickening. There was overall retinal thickening or nor-
mal thickness despite outer nuclear layer thinning. Inner nu-
clear layer thickening was sometimes prominent (for example,
family 1, P6, LE at many ages; family 2, P5, LE at age 21; and
family 3, P1, RE). The patients we studied with cystic macular
changes had visual acuities of 20/30 or better despite different
dimensions of foveal lesions. This is consistent with an earlier
study in RP which reported no relationship between visual
acuity and foveal thickness, unlike in diabetic macular edema.
A statistically significant relationship between the width of the
lesions and acuity was found.27The width of cystic abnormal-
ity was not quantified in the present work. A foveal structural
detail for correlation with visual acuity may be the vitread
ORCC component associated
OS.20,22,23,25This OCT feature was present in the USH2 pa-
tients of this study.
The basis of macular edema in USH or nonsyndromic RP is
poorly understood. The site of the breakdown of the blood–
retinal barrier in RP has been investigated clinically with a
number of techniques and variously considered as either at the
retinal pigment epithelium or the perifoveal capillary plexus or
both.62,65,66A histopathologic study of eyes with RP led to the
conclusion that the main site of permeability was the retinal
vasculature.67It is unknown whether the USHs have a specific
abnormality in regulation of blood–retinal barrier permeability
or there is some shared mechanism with RP and other retinal
diseases, such as release of growth factors during retinal de-
generation and altered vascular permeability.59,68–70
Histamine is among the soluble factors suspected to be
mediators of blood–retinal barrier dysfunction in diabe-
tes.68,71,72It is thus of interest that there was an unexpected
and dramatic reduction of longstanding macular cystic change
in a USH2C patient who was taking oral antihistamines (H1
receptor antagonists). Experimental and pilot human data in
diabetes support an effect on blood–retinal barrier permeabil-
ity of an H1 receptor antagonist.73,74The reduction of macular
cystic abnormality in our single case does not justify therapeu-
tic recommendations, but warrants further study. If antihista-
mines could improve macular structure at doses usually rec-
ommended for allergic symptoms, then it may be worth
considering as a useful primary or adjuvant therapy or after
rebound of macular edema after carbonic anhydrase inhibitor
use in USH or RP.75–77
The authors thank Andy Cheung, John Chico, Vaibhav Bhuva, Alex-
ander Pantelyat, Yijun Huang, Daniel Marks, Michael Pianta, Alyson
Walsh, Boram Kim, Paul Schied, David Hanna, Laurie Seltzer, Leigh
Gardner, Jean Andorf and Jessica Emmons for help with the study.
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