December 2008
Volume 49, Issue 12
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Retina  |   December 2008
Disease Course in Patients with Autosomal Recessive Retinitis Pigmentosa due to the USH2A Gene
Author Affiliations
  • Michael A. Sandberg
    From the The Berman-Gund Laboratory for the Study of Retinal Degenerations and
  • Bernard Rosner
    From the The Berman-Gund Laboratory for the Study of Retinal Degenerations and
  • Carol Weigel-DiFranco
    From the The Berman-Gund Laboratory for the Study of Retinal Degenerations and
  • Terri L. McGee
    From the The Berman-Gund Laboratory for the Study of Retinal Degenerations and
    The Ocular Molecular Genetics Institute, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts.
  • Thaddeus P. Dryja
    The Ocular Molecular Genetics Institute, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts.
  • Eliot L. Berson
    From the The Berman-Gund Laboratory for the Study of Retinal Degenerations and
Investigative Ophthalmology & Visual Science December 2008, Vol.49, 5532-5539. doi:10.1167/iovs.08-2009
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      Michael A. Sandberg, Bernard Rosner, Carol Weigel-DiFranco, Terri L. McGee, Thaddeus P. Dryja, Eliot L. Berson; Disease Course in Patients with Autosomal Recessive Retinitis Pigmentosa due to the USH2A Gene. Invest. Ophthalmol. Vis. Sci. 2008;49(12):5532-5539. doi: 10.1167/iovs.08-2009.

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      © 2017 Association for Research in Vision and Ophthalmology.

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Abstract

purpose. To estimate the mean rates of ocular function loss in patients with autosomal recessive retinitis pigmentosa due to USH2A mutations.

methods. In 125 patients with USH2A mutations, longitudinal regression was used to estimate mean rates of change in Snellen visual acuity, Goldmann visual field area (V4e white test light), and 30-Hz (cone) full-field electroretinogram amplitude. These rates were compared with those of previously studied cohorts with dominant retinitis pigmentosa due to RHO mutations and with X-linked retinitis pigmentosa due to RPGR mutations. Rates of change in patients with the Cys759Phe mutation, the USH2A mutation associated with nonsyndromic disease, were compared with rates of change in patients with the Glu767fs mutation, the most common USH2A mutation associated with Usher syndrome type II (i.e., retinitis pigmentosa and hearing loss).

results. Mean annual exponential rates of decline for the USH2A patients were 2.6% for visual acuity, 7.0% for visual field area, and 13.2% for electroretinogram amplitude. The rate of acuity loss fell between the corresponding rates for the RHO and RPGR patients, whereas the rates for field and ERG amplitude loss were faster than those for the RHO and RPGR patients. No significant differences were found for patients with the Cys759Phe mutation versus patients with the Glu767fs mutation.

conclusions. On average, USH2A patients lose visual acuity faster than RHO patients and slower than RPGR patients. USH2A patients lose visual field and cone electroretinogram amplitude faster than patients with RHO or RPGR mutations. Patients with a nonsyndromic USH2A mutation have the same retinal disease course as patients with syndromic USH2A disease.

Mutations in the genes encoding rhodopsin (RHO), retinitis pigmentosa GTPase regulator (RPGR), and usherin (USH2A) are the most common causes of retinitis pigmentosa, each gene accounting for approximately 10% of cases in North America. 1 2 3 We have reported differences in the mean rates of loss of visual acuity, visual field, and ERG amplitude between patients with RHO mutations and patients with RPGR mutations. 4 The present study was conducted to determine the rates of progression for patients with USH2A mutations and compare them with those previously reported for the other two common forms of retinitis pigmentosa. 
In 1998, mutations in the USH2A gene were first reported as a cause of Usher syndrome type II, an autosomal recessive form of retinitis pigmentosa with mild-to-moderate congenital hearing loss and normal vestibular function, 5 based on analysis of the 21 exons found to encode a USH2A transcript. 6 A longer transcript consisting of 51 additional 3′ exons was more recently identified, and mutations causing Usher syndrome type II were also found in these exons. 7 Most USH2A mutations individually account for only a few percent of cases of Usher syndrome type II. An exception is the mutation c.2299delG (Glu767fs) in exon 13 which is geographically widespread and found to have been derived from a common ancestor. 8 In addition, another common mutation in this gene—Cys759Phe, also in exon 13—has been reported to cause 4% to 5% of autosomal recessive retinitis pigmentosa without hearing loss. 9 10 Because in many cases this mutation in one allele does not cause hearing loss even when combined with a pathogenic USH2A mutation in the second allele, 9 10 we hypothesized that a patient with at least one allele carrying the Cys759Phe mutation might have a less severe ocular disease course than patients with other USH2A mutations. To test this hypothesis, we also compared mean rates of decline of patients with the Cys759Phe mutation with those of patients with the Glu767fs mutation. We restricted this comparison to patients who carried the one mutation without carrying the other. 
Methods
Patients
This study adhered to the tenets of the Declaration of Helsinki and was approved by the Institutional Review Boards of the Massachusetts Eye and Ear Infirmary and Harvard Medical School. Our USH2A longitudinal dataset comprised 125 patients with pathogenic mutations. This cohort (mean age at baseline: 31.6 years, age range at baseline: 6–59 years) had 3 to 27 years of follow-up from 1975 to 2005 using the same test conditions with a mean follow-up of 10.4 years and an average of 7.4 ocular examinations/patient. All patients had parents with no history of retinitis pigmentosa, and we therefore presumed that the condition in these patients was autosomal recessive. The RHO and RPGR longitudinal datasets, derived from a previous study, 2 were also limited to patients with at least 3 years of follow-up. They yielded a sample of 134 RHO patients (mean age at baseline: 36.0 years, age range at baseline: 8–66 years) who had been observed for 3 to 24 years with an average follow-up of 8.9 years based on an average of 6.2 examinations/patient and 113 RPGR patients (mean age at baseline: 26.1 years, age range at baseline: 5–61 years) who had been observed for 3 to 28 years with an average follow-up of 9.8 years based on an average of 7.2 examinations/patient. The mean age at baseline of the patients varied significantly by group (P < 0.001). 
Clinical Evaluation
All the patients underwent identical ocular examinations and quantification of data, as described in detail previously. 4 We recorded best corrected Snellen visual acuities and coded them as decimals. Kinetic visual fields were measured to the V4e white test light against the standard background of 31.5 apostilbs. Fields were plotted with a digitizing tablet or scanned by custom software and converted to areas in deg2. We placed a contact lens electrode on the topically anesthetized cornea and elicited full-field cone ERGs with 10 μs, 30-Hz flashes of white light (0.2 cd-s/m2) after pupillary dilation and 45 minutes of dark adaptation. Digital filtering and signal averaging were used to quantify responses <10 μV in amplitude. As part of another research project, 11 we had recorded optical coherence tomograms (OCTs) from four of the patients with the Glu767fs mutation (age range: 43–54 years) who had visual acuities spanning 20/20 to 20/70. We evaluated these tomograms to try to reveal the morphologic basis for visual acuity loss in this disease. 
Statistical Analyses
We censored visual acuities, visual field areas, and ERG amplitudes from selected visits to minimize ceiling and floor effects, converted these measures to natural logarithms, and performed analyses as described previously. 4 In addition, we excluded USH2A patients from visual field analyses if they showed marked inconsistency over the course of follow-up, possibly due to an impaired ability to hear the examiner’s prompts. Specifically, we eliminated patients if the root mean square error from the regression of loge visual field area on time exceeded 4 SD from the grand mean. Altogether, we excluded 23 patients from the analysis of visual acuity change, 16 patients from the analysis of visual field change, and 56 patients from the analysis of ERG change. 
We used repeated-measures longitudinal regression (PROC MIXED, SAS, ver. 9, SAS Institute, Cary, NC) to estimate the mean rate of change for each outcome measure based on the average loge value for one or both eyes at each visit and compared mean slopes for patients by genotype. We fit a Weibull function to survival data (PROC LIFEREG; SAS) to compare the age distribution for legal blindness (i.e., a visual acuity of 20/200 or worse or a visual field diameter of 20° or less in each eye) in patients by genotype. This procedure accounts for left censoring (i.e., patients who were legally blind at the baseline visit), right censoring (i.e., patients who had not become legally blind by the last follow-up visit), and interval censoring (i.e., patients who became legally blind between two follow-up visits). 
Results
USH2A Mutations
Table 1lists the nucleotide change and protein change for each of the 38 mutations identified in the patients included in the study. Many of these mutations were reported previously as the result of a screen of the short isoform of USH2A. 3 Subsequently, we screened additional patients, including the exons for the long isoform, and found 18 novel mutations (indicated in bold in Table 1 ). 
Table 2lists the identified mutations by patient. Not all patients were screened for mutations in the entire gene, and some patients carried a rare USH2A missense change that was not demonstrably pathogenic. These factors probably account for the high prevalence of patients with only one detected pathogenic mutation in our series. The table shows that 41 patients (33%) had the Cys759Phe mutation, associated with nonsyndromic retinitis pigmentosa, and not the Glu767fs mutation, associated with hearing loss. Conversely, 43 patients (34%) had the Glu767fs mutation and not the Cys759Phe mutation. 
Baseline Ocular Function
Table 2also reveals that at a mean age of 32 years, our USH2A patients had mean visual acuities that were reduced one to two lines, mean visual fields that were reduced approximately 40% below normal, and mean cone ERG amplitudes that were reduced nearly 90% below normal. 
Mean Rates of Change
Table 3lists the mean annual loge rates of change in patients with USH2A mutations, along with standard errors and significance levels. The mean loge values correspond to mean annual exponential rates of decline of 2.6% for Snellen visual acuity, 7.0% for visual field area to the V4e test light, and 13.2% for cone ERG amplitude to 30 Hz flashes. In comparison, the patients with RHO or RPGR mutations, respectively, had mean annual exponential rates of decline of 1.6% and 4.0% for visual acuity, 2.9% and 4.7% for visual field area, and 7.7% and 7.1% for cone ERG amplitude. The mean rate of visual acuity loss in the USH2A patients was significantly faster than that in the RHO patients (P = 0.005), but significantly slower than that in the RPGR patients (P < 0.001). On the other hand, the mean rate of visual field loss and the mean rate of ERG amplitude loss in the USH2A patients were significantly faster than the corresponding rates in the RHO and the RPGR patients (P < 0.001 in all cases). 
We then compared mean rates of change in USH2A patients with the Cys759Phe mutation (and not the Glu767fs mutation) to the mean rates in USH2A patients with the Glu767fs mutation (and not the Cys759Phe mutation). Mean rates of annual decline were, respectively, 2.9% versus 2.1% for visual acuity, 6.9% versus 7.7% for visual field area, and 13.1% versus 12.9% for ERG amplitude. None of these differences was statistically significant. 
Distributions of Rate of Change
Figures 1 2to 3show the distributions of annual rate of change by ocular function and genotype. The x-axes are all spaced in intervals of 0.1 loge unit (i.e., ∼10%) and, for a given measure of ocular function, span the same range. The modal values provide a gauge of the variation in rate of change and represent 60.6% to 61.8% of cases for visual acuity, 47.6% to 54.7% of cases for visual field area, and 33.3% to 40.4% of cases for cone ERG amplitude. Even though these modal values, on average, represent only about half of each group of change scores, it is still possible to discern differences in these distributions that parallel the mean differences cited. With the location of the mode on the x-axis for the USH2A patients as reference, the cumulative percentage of cases to the left of this value (i.e., associated with faster progression) for visual acuity is 9.9% in USH2A patients, 6.7% in RHO patients, and 19.5% in RPGR patients. The cumulative percentage of cases to the left of the USH2A mode for visual field area is 31.2% in USH2A patients, 11% in RHO patients, and 19.5% in RPGR patients. The cumulative percentage of cases to the left of the USH2A mode for cone ERG amplitude is 37.6% in USH2A patients, 12.3% in RHO patients, and 15.1% in RPGR patients. Thus, the visual acuity distribution in the USH2A patients tends to lie between those of the RHO patients and RPGR patients, whereas the visual field and ERG distributions in the USH2A patients tend to be to the left of the corresponding distributions for the RHO and the RPGR patients—similar to that observed for mean rates of change. 
Median Age to Reach Legal Blindness
We found a significant effect of genotype on the age distribution for legal blindness (P < 0.001). Our patients with USH2A mutations reached legal blindness, based on loss of acuity or field, at a median age of 58 years (Fig. 4) ; this age is between those previously reported for the patients with RPGR mutations (45 years) and for the patients with RHO mutations (77 years). 4 When visual acuity and visual field survival were considered separately, patients with USH2A mutations failed at a median age of 65 years for both measures of ocular function (Fig. 4)
OCTs in Patients with the Glu767fs Mutation
Figure 5illustrates tomograms recorded from a normal control and four patients with the USH2A Glu767fs mutation. In contrast to the normal tomogram, all four patients show a loss of the outer nuclear layer (ONL) outside of the fovea. In addition, the thickness of the ONL in the foveal center is smaller for eyes with lower visual acuity in this sample, and the patient with a visual acuity of 20/50 has small off-center cysts. 
Discussion
The present study shows that patients with retinitis pigmentosa due to USH2A mutations, on average, lost Snellen visual acuity more quickly (i.e., 2.6%/year or ∼0.6 letter/year) than patients with RHO mutations (i.e., 1.6%/year or ∼0.4 letter/year) but more slowly than patients with RPGR mutations (i.e., 4.0%/year or ∼0.9 letter/year). On the other hand, the USH2A patients lost visual field area and full-field cone ERG amplitude, which reflect predominantly extrafoveal function, more rapidly than the other two groups. These differences in mean rates of change could be detected even though patients within a given genotype and for a particular measure of ocular function showed some variation in their rates of change. These results provide a framework for planning clinical trials aimed at stabilizing or slowing the course of this condition. 
Two previous studies also evaluated rates of loss of ocular function in patients with USH2A mutations. One of these studies followed Snellen visual acuity in six patients and Goldmann visual field in four patients but quantified results in “functional” value units that cannot readily be compared to the standard measurements used in the present study. 12 The second study followed visual field area in eight patients with the Glu767fs mutation, censoring areas above their lower limit of normal and data “… that deviated from both preceding and succeeding field areas by 50% or more …” regardless of the intervening time interval. 13 These patients had an average rate of decline to the V4e stimulus of 12.1%/year, faster than that observed in our patients with this mutation (7.7%/year), possibly due to methodological differences. Contrary to our initial hypothesis, we found that patients with the Cys759Phe mutation, associated with nonsyndromic disease, did not have a significantly slower course of disease than patients with the Glu767fs mutation, associated with Usher syndrome type II. 
Our data also revealed that patients with USH2A mutations become legally blind due to loss of visual acuity or visual field at a median age that is older than that of patients with RPGR mutations and younger than that of patients with RHO mutations. Loss of visual acuity and loss of visual field equally contributed to our USH2A patients becoming legally blind. This distinguishes them from RPGR patients, who generally become legally blind due to loss of visual acuity, and RHO patients, who generally become legally blind due to loss of visual field. 4  
The tomograms recorded in patients with the USH2A Glu767fs mutation showed thinning and loss of the ONL with increasing eccentricity consistent with central visual field constriction, thinning of the ONL in the center in parallel with decreased visual acuity, and macular cysts in one case. These changes are typical of those that have been described in patients with different forms of retinitis pigmentosa. 4 11 14  
 
Table 1.
 
USH2A Mutations in DNA and Protein Format
Table 1.
 
USH2A Mutations in DNA and Protein Format
Exon/Intron Nucleotide Change Protein Change
3 c.545_546delAA Lys182fs
6 c.920_923dupGCCA His308fs
6 c.1026_29delCTCT Ser343fs*
6 c.1110_1111delTA Ile371fs
7 c.1214delA Asn405fs
7 c.1256G>T Cys419Phe
Intron 10 c.1841-2A>G Alters splice site IVS10-2A>G
11 c.1876C>T Arg626X
12 c.2073C>A Cys691X
12 c.2100delG Thr701fs*
Intron 12 c.2168-1G>C Alters splice site IVS12-1G>C
13 c.2276G>T Cys759Phe
13 c.2299delG Glu767fs
13 c.2761del C Leu921fs
16 c.3187_3188delCA Gln1063fs
20 c.4314delG Ile1439fs
20 c.4338_39delCT Cys1447fs
21 c.4510_4511insA Arg1504fs
22 c.4645C>T Arg1549X
26 c.5191_5192delAT Met1731fs
Intron 28 c.5775+1G>A Alters splice site IVS28+1G>A
Intron 29 c.5857+1G>C Alters splice site IVS29+1G>C
Intron 29 c.5857+2T>C Alters splice site IVS29+2T>C
30 c.5933_5940delCTGTTGTC Pro1978fs
32 c.6169C>T Gln2057X
40 c.7493delG Ser2498fs
41 c.8167C>T Arg2723X
42 c.8557A>T Arg2853X
44 c.8834G>A Trp2945X
48 c.9424G>T Gly3142X
52 c.10190_10191delAA Lys3397fs
59 c.11533C>T Gln3845X
61 c.11864G>A Trp3955X
Intron 61 c.12067-2A>G Alters splice site IVS61-2A>G
64 c.14010_14062del Glu4671fs
64 c.14131C>T Gln4711X
68 c.14803C>T Arg4935X
68 c.14879_c.14880delAAins45 Gln4960fs
Table 2.
 
Baseline Ocular Function of Patients with USH2A Mutations
Table 2.
 
Baseline Ocular Function of Patients with USH2A Mutations
ID Mutation (Exon) Mutation (Exon) Age (y) VA OD* VA OS* VF OD, † VF OS, † ERG OD, ‡ ERG OS, ‡
19238 Lys182fs (3) Glu767fs (13) 24 20/100 20/70 6,438 5,205 0.61 0.48
22085 His308fs (6) Trp3955X (61) 59 20/200 20/200 152 213 0.30 0.15
19083 His308fs (6) 15 20/30 20/30 10,451 8,768 1.89 1.82
06863 Ser343fs (6) 34 20/50 20/60 384 279 0.30 0.30
02933 Ile371fs (6) 31 20/30 20/40 1,073 585  NA  NA
19824 Asn405fs (7) 26 20/30 20/30 3,795 3,457 0.73 0.61
06236 Cys419Phe (7) 28 20/40 20/40 14,349 15,336 3.04 3.72
19477 Cys419Phe (7) IVS10-2A>G (I-10) 44 20/40 20/40 410 545 0.08 0.31
00304 Cys419Phe (7) 35 20/25 20/25 10,716 10,322 6.00 6.00
07018 Cys419Phe (7) 30 20/30 20/30 16,134 15,672 2.86 2.62
13287 Arg626X (11) Arg626X (11) 32 20/25 20/25 3,700 3,610 0.23 0.09
15597 Arg626X (11) Cys1447fs (20) 20 20/30 20/30 NA NA 2.31 1.75
13574 Cys691X (12) Glu767fs (13) 25 20/20 20/20 8,157 7,770 0.90 0.90
14419 Thr701fs (12) Gly3142X (48) 17 20/20 20/30 6,926 4,379 0.45 0.37
01376 IVS12-1G>C (I-12) 53 20/30 20/40 NA NA  NA  NA
05831 Cys759Phe (13) 43 20/40 20/50 1,576 1,646 0.26 0.24
13445 Cys759Phe (13) Trp3955X (61) 28 20/30 20/30 NA NA 29.40 29.40
15657 Cys759Phe (13) Cys759Phe (13) 36 20/25 20/50 10,920 9,497 9.24 4.20
11572 Cys759Phe (13) Cys759Phe (13) 15 20/30 20/30 7,711 9,867 0.41 0.55
05014 Cys759Phe (13) Cys759Phe (13) 35 20/40 20/30 9,132 8,980 22.00 22.00
06705 Cys759Phe (13) Glu767fs (13) 28 20/25 20/25 21,176 23,087 13.74 12.71
05918 Cys759Phe (13) Glu767fs (13) 40 20/30 20/30 8,367 8,174 7.48 9.13
06475 Cys759Phe (13) Glu767fs(13) 32 20/40 20/40 1,556 1,117 2.07 1.83
06792 Cys759Phe (13) Cys1447fs (20) 33 20/20 20/20 4,288 3,258 3.19 2.36
07889 Cys759Phe (13) Cys1447fs (20) 27 20/20 20/20 8,243 7,725 29.40 52.94
11439 Cys759Phe (13) Cys1447fs (20) 28 20/20 20/20 10,077 11,732 10.64 14.00
14338 Cys759Phe (13) Pro1978fs (30) 36 20/20 20/25 7,600 7,944 0.20 0.11
14436 Cys759Phe (13) IVS29+2T>C (I-29) 43 20/20 20/40 12,170 12,186 23.50 20.60
14483 Cys759Phe (13) 38 20/20 20/20 6,934 6,403 29.40 23.50
06966 Cys759Phe (13) 44 20/30 20/30 4,245 4,077 11.69 8.06
05666 Cys759Phe (13) 44 20/20 20/20 9,554 9,787 1.20 1.90
03458 Cys759Phe (13) Glu4671fs (64) 34 20/25 20/25 4,703 4,488  NA  NA
15221 Cys759Phe (13) 34 20/20 20/20 8,843 8,927 7.79 11.40
19431 Cys759Phe (13) 21 20/30 20/30 15,970 16,092 19.6 18.2
06191 Cys759Phe (13) 33 20/30 20/30 2,751 3,039 0.09 0.21
05917 Cys759Phe (13) 38 20/20 20/25 17,802 20,246 5.08 4.99
05907 Cys759Phe (13) 35 20/25 20/25 5,312 4,899 1.89 1.32
07008 Cys759Phe (13) 43 20/60 20/100 196 231 0.16 0.13
06898 Cys759Phe (13) 40 20/30 20/30 9,763 9,364 1.13 2.62
05967 Cys759Phe (13) 33 20/20 20/20 402 583 1.21 0.77
03753 Cys759Phe (13) 33 20/30 20/50 12,960 10,952 59.0 59.0
02874 Cys759Phe (13) 33 20/25 20/25 10,191 10,172 6.00 6.00
07065 Cys759Phe (13) 45 20/30 20/30 16,342 17,005 6.25 6.12
00220 Cys759Phe (13) 40 20/25 20/20 10,102 9,972  NA  NA
05377 Cys759Phe (13) 41 20/25 20/30 8,560 9,000 14.0 8.40
06144 Cys759Phe (13) 38 20/30 20/25 1,572 490 0.33 0.18
06210 Cys759Phe (13) 37 20/50 20/60 2,555 1,449 1.80 2.08
06732 Cys759Phe (13) 32 20/30 20/30 175 227 3.41 2.54
07879 Cys759Phe (13) 45 20/40 20/30 3,148 3,377 23.5 11.00
13613 Cys759Phe (13) 26 20/25 20/25 98 733 1.30 2.50
11259 Cys759Phe (13) 28 20/20 20/20 6,154 8,217 1.40 5.04
11505 Cys759Phe (13) 25 20/25 20/25 8,759 7,407 1.50 0.52
05011 Cys759Phe (13) 33 20/20 20/20 11,992 10,804 11.00 21.0
13115 Cys759Phe (13) 44 20/20 20/20 8,155 9,740 1.20 1.90
14027 Cys759Phe (13) 32 20/25 20/20 13,887 12,868 23.50 23.50
02726 Cys759Phe (13) 55 20/30 20/30 7,391 6,701 11.00 11.00
02943 Cys759Phe (13) 23 20/30 20/25 9,294 8,715  NA  NA
02954 Cys759Phe (13) 45 20/20 20/20 1,001 1,460  NA 12.0
00994 Cys759Phe (13) 36 20/40 20/50 366 264  NA  NA
15169 Glu767fs (13) 17 20/25 20/25 7,686 8,028 0.35 0.21
11451 Glu767fs (13) Gln4960fs (68) 27 20/20 20/20 9,997 10,274 1.19 1.40
22045 Glu767fs (13) Glu767fs (13) 27 20/50 20/50 6,141 4,992 1.87  NA
02265 Glu767fs (13) Cys1447fs (20) 17 20/25 20/50 5,415 5,654  NA  NA
02267 Glu767fs (13) Cys1447fs (20) 16 20/25 20/30 7,430 7,106  NA  NA
02266 Glu767fs (13) Cys1447fs (20) 15 20/20 20/20 10,467 9,806 62.0  NA
19249 Glu767fs (13) Arg1549X (22) 22 20/20 20/20 3,802 2,508 0.80 0.53
15499 Glu767fs (13) Arg2853X (42) 24 20/30 20/30 6,201 7,648 0.80 0.88
05958 Glu767fs (13) 37 20/30 20/30 12,011 12,341 8.00 8.00
11300 Glu767fs (13) IVS29+1G>C (I-29) 45 20/40 20/40 290 523 0.20 0.20
19281 Glu767fs (13) IVS61-2A>G (I-61) 44 20/25 20/20 3,329 1,618 2.35 1.91
06991 Glu767fs (13) 40 20/25 20/30 9,672 12,803 0.96 0.93
06724 Glu767fs (13) 31 20/40 20/40 12,591 11,592 1.10 0.92
05148 Glu767fs (13) 40 20/30 20/200 8,558 7,642 2.72 1.79
15297 Glu767fs (13) 45 20/60 20/25 11,342 10,503 5.87 4.56
15375 Glu767fs (13) 47 20/25 20/25 11,456 11,815 1.98 1.44
06704 Glu767fs (13) 24 20/30 20/40 10,999 7,670 35.9 34.2
06750 Glu767fs (13) 32 20/30 20/40 3,447 2,591 4.32 4.02
06178 Glu767fs (13) 36 20/40 20/25 650 881 0.56 0.48
06226 Glu767fs (13) 26 20/30 20/30 8,477 9,762 1.25 1.42
06256 Glu767fs (13) Arg1549X (22) 27 20/25 20/30 3,900 4,100 0.31 0.33
06650 Glu767fs (13) 33 20/20 20/25 13,164 11,544 1.62 1.81
06666 Glu767fs (13) 23 20/25 20/25 944 888 0.51 0.85
05751 Glu767fs (13) 23 20/30 20/20 5,306 5,518 0.32 0.47
06017 Glu767fs (13) 31 20/25 20/25 4,705 3,610 5.37 4.65
05916 Glu767fs (13) 39 20/25 20/30 4,140 5,787 1.96 1.96
03960 Glu767fs (13) 17 20/40 20/30 11,182 10,842 1.04 0.77
06798 Glu767fs (13) 32 20/25 20/25 14,005 15,158 2.05 1.38
05556 Glu767fs (13) 19 20/25 20/25 11,028 15,047 0.26 0.35
05213 Glu767fs (13) 15 20/20 20/20 7,774 8,778 1.05 1.08
02130 Glu767fs (13) 21 20/20 20/25 3,122 3,561 0.94 0.94
07031 Glu767fs (13) 26 20/30 20/40 14,551 13,448 1.15 0.77
02510 Glu767fs (13) 26 20/30 20/25 565 2,407 6.00 6.00
03193 Glu767fs (13) 28 20/20 20/20 638 690  NA  NA
05800 Glu767fs (13) 42 20/50 20/50 1,798 2,151 0.22 0.34
05785 Glu767fs (13) 27 20/30 20/25 14,130 17,982 3.52 3.07
07401 Glu767fs (13) 39 20/40 20/30 283 332 0.16 0.16
05252 Glu767fs (13) Arg4935X (68) 42  NA  NA 9,897 9,504  NA  NA
14015 Glu767fs (13) 25 20/20 20/20 9,755 10,317 17.60 20.60
01445 Glu767fs (13) 54 20/30 20/30 10,561 10,759 0.25 0.67
15938 Glu767fs (13) 29 20/30 20/40 7,220 7,556 0.74 0.60
15579 Glu767fs (13) 31 20/25 20/25 8,868 6,637 1.12 0.87
19822 Glu767fs (13) 52 20/40 20/60 168 138 0.14 0.11
05766 Leu921fs (13) Cys1447fs (20) 30 20/25 20/20 973 1,400 0.49 0.68
15285 Gln1063fs (16) Trp2945X (44) 22 20/25  NA 6,457 4,376  NA  NA
05960 Gln1408X (19) 33 20/25 20/25 3,974 5,820  NA  NA
07916 Ile1439fs (20) 30 20/20 20/20  NA  NA 0.50 0.70
04129 Cys1447fs (20) 6 20/40 20/30 10,261 11,787  NA  NA
04032 Cys1447fs (20) 7 20/40 20/30 4,839 4,754  NA  NA
03482 Cys1447fs (20) 19 20/30 20/30 10,576 11,651  NA  NA
06241 Cys1447fs (20) 36 20/30 20/30 13,131 7,372 11.96 12.59
07607 Cys1447fs (20) Arg4935X (68) 15 20/20 20/20 10,117 10,547  NA 1.40
11719 Cys1447fs (20) Cys1447fs (20) 27 20/25 20/25 9,121 9,317 1.10 1.10
06019 Cys1447fs (20) 40 20/50 20/50 489 421 0.10 0.12
06088 Arg1504fs (21) 20 20/25 20/25 1,572 1,410 0.20 0.30
03811 Arg1549X (22) 31 20/30 20/40 2,925 3,961  NA  NA
05857 Met1731fs (26) 39 20/70 20/100 14,753 14,331 3.14 2.50
07278 Gln2057X (32) 22 20/20 20/30 8,943 10,503 0.60 0.20
05558 Ser2498fs (40) 34 20/25 20/30 11,524 10,354 3.02 2.42
14888 Arg2723X (41) Arg2723X (41) 43 20/400 20/80 186 172 0.10  NA
00943 Arg2723X (41) 36 20/50 HM 234 198 0.17 0.10
03541 Gly3142X (48) 29 20/30 20/25 434 347  NA  NA
04132 Lys3397fs (52) IVS28+1G>A (I-28) 30 HM 20/50  NA 8,261  NA  NA
14402 Gln3845X (59) Gln3845X (59) 18 20/30 20/25 4,605 3,266 0.23 0.16
05765 Trp3955X (61) 24 20/30 20/50 110 129 0.29 0.33
14518 Gln4711X (64) 22 20/20 20/25 12,843 13,452 4.90 3.60
Arithmetic mean 31.6 20/28 20/29 7,003 6,987 5.91 5.50
Number of patients with values 125 124 123 120 121 105 104
Table 3.
 
Annual Rates of Change in Patients with USH2A Mutations
Table 3.
 
Annual Rates of Change in Patients with USH2A Mutations
Ocular Function n * Mean ± SEM (Geometric Mean), † P , †
Loge visual acuity 102 −0.026 ± 0.002 (−2.6%) <0.001
Loge visual field area 109 −0.074 ± 0.003 (−7.0%) <0.001
Loge ERG amplitude 69 −0.141 ± 0.005 (−13.2%) <0.001
Figure 1.
 
Distributions of rate of change of visual acuity by genotype. Represented are 102 patients with USH2A mutations, 89 patients with RHO mutations, and 93 patients with RPGR mutations.
Figure 1.
 
Distributions of rate of change of visual acuity by genotype. Represented are 102 patients with USH2A mutations, 89 patients with RHO mutations, and 93 patients with RPGR mutations.
Figure 2.
 
Distributions of rate of change of visual field area by genotype. Represented are 109 patients with USH2A mutations, 128 patients with RHO mutations, and 103 patients with RPGR mutations.
Figure 2.
 
Distributions of rate of change of visual field area by genotype. Represented are 109 patients with USH2A mutations, 128 patients with RHO mutations, and 103 patients with RPGR mutations.
Figure 3.
 
Distributions of rate of change of cone ERG amplitude by genotype. Represented are 69 patients with USH2A mutations, 89 patients with RHO mutations, and 66 patients with RPGR mutations.
Figure 3.
 
Distributions of rate of change of cone ERG amplitude by genotype. Represented are 69 patients with USH2A mutations, 89 patients with RHO mutations, and 66 patients with RPGR mutations.
Figure 4.
 
Weibull survival analysis plot for age to legal blindness (i.e., visual acuity ≤ 20/200 or visual field equivalent diameter4 ≤ 20°), to visual acuity ≤ 20/200, and to visual field equivalent diameter ≤ 20° among patients with USH2A mutations. Vertical dashed lines: median ages for legal blindness.
Figure 4.
 
Weibull survival analysis plot for age to legal blindness (i.e., visual acuity ≤ 20/200 or visual field equivalent diameter4 ≤ 20°), to visual acuity ≤ 20/200, and to visual field equivalent diameter ≤ 20° among patients with USH2A mutations. Vertical dashed lines: median ages for legal blindness.
Figure 5.
 
Tomograms from a normal subject and from four patients (ages 54, 45, 43, and 52 years from top to bottom) with retinitis pigmentosa (RP) due to the Glu767fs mutation. Images span 6 mm horizontally. Arrow: low-reflectance outer nuclear layer (ONL) visible over the full 6 mm in the normal tomogram, in contrast to what is seen in the patient tomograms.
Figure 5.
 
Tomograms from a normal subject and from four patients (ages 54, 45, 43, and 52 years from top to bottom) with retinitis pigmentosa (RP) due to the Glu767fs mutation. Images span 6 mm horizontally. Arrow: low-reflectance outer nuclear layer (ONL) visible over the full 6 mm in the normal tomogram, in contrast to what is seen in the patient tomograms.
DryjaTP, McEvoyJA, McGeeTL, BersonEL. Novel rhodopsin mutations Gly114Val and Gln184Pro in dominant retinitis pigmentosa. Invest Ophthalmol Vis Sci. 2000;41:3124–3127. [PubMed]
SharonD, SandbergMA, RabeVW, et al. RP2 and RPGR mutations and clinical correlations in patients with X-linked retinitis pigmentosa. Am J Hum Genet. 2003;73:1131–1146. [CrossRef] [PubMed]
SeyedahmadiBJ, RivoltaC, KeeneJA, et al. Comprehensive screening of the USH2A gene in Usher syndrome type II and non-syndromic recessive retinitis pigmentosa. Exp Eye Res. 2004;79:167–173. [CrossRef] [PubMed]
SandbergMA, RosnerB, Weigel-DiFrancoC, et al. Disease course of patients with X-linked retinitis pigmentosa due to RPGR gene mutations. Invest Ophthalmol Vis Sci. 2007;48:1298–1304. [CrossRef] [PubMed]
EudyJD, WestonMD, YaoS, et al. Mutation of a gene encoding a protein with extracellular matrix motifs in Usher syndrome type IIa. Science. 1998;280:1753–1757. [CrossRef] [PubMed]
WestonMD, EudyJD, FujitaS, et al. Genomic structure and identification of novel mutations in usherin, the gene responsible for Usher syndrome type IIa. Am J Hum Genet. 2000;66:1199–1210. [CrossRef] [PubMed]
van WijkE, PenningsRJ, te BrinkeH, et al. Identification of 51 novel exons on the Usher syndrome type 2A (USH2A) gene that encode multiple conserved functional domains and that are mutated in patients with Usher syndrome type II. Am J Hum Genet. 2004;74:738–744. [CrossRef] [PubMed]
DreyerB, TranebjaergL, BroxV, et al. A common ancestral origin of the frequent and widespread 2299delG USH2A mutation. Am J Hum Genet. 2001;69:228–234. [CrossRef] [PubMed]
RivoltaC, SwekloEA, BersonEL, DryjaTP. Missense mutation in the USH2A gene: association with recessive retinitis pigmentosa without hearing loss. Am J Hum Genet. 2000;66:1975–1978. [CrossRef] [PubMed]
BernalS, AyusoC, AntinoloG, et al. Mutations in USH2A in Spanish patients with autosomal recessive retinitis pigmentosa: high prevalence and phenotypic variation. J Med Genet. 2003;40:e8. [CrossRef] [PubMed]
SandbergMA, BrockhurstRJ, GaudioAR, BersonEL. The association between visual acuity and central retinal thickness in retinitis pigmentosa. Invest Ophthalmol Vis Sci. 2005;46:3349–3354. [CrossRef] [PubMed]
PenningsRJE, HuygenPLM, OrtenDJ, et al. Evaluation of visual impairment in Usher syndrome 1b and Usher syndrome 2a. Acta Ophthalmol Scand. 2004;82:131–139. [CrossRef] [PubMed]
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Figure 1.
 
Distributions of rate of change of visual acuity by genotype. Represented are 102 patients with USH2A mutations, 89 patients with RHO mutations, and 93 patients with RPGR mutations.
Figure 1.
 
Distributions of rate of change of visual acuity by genotype. Represented are 102 patients with USH2A mutations, 89 patients with RHO mutations, and 93 patients with RPGR mutations.
Figure 2.
 
Distributions of rate of change of visual field area by genotype. Represented are 109 patients with USH2A mutations, 128 patients with RHO mutations, and 103 patients with RPGR mutations.
Figure 2.
 
Distributions of rate of change of visual field area by genotype. Represented are 109 patients with USH2A mutations, 128 patients with RHO mutations, and 103 patients with RPGR mutations.
Figure 3.
 
Distributions of rate of change of cone ERG amplitude by genotype. Represented are 69 patients with USH2A mutations, 89 patients with RHO mutations, and 66 patients with RPGR mutations.
Figure 3.
 
Distributions of rate of change of cone ERG amplitude by genotype. Represented are 69 patients with USH2A mutations, 89 patients with RHO mutations, and 66 patients with RPGR mutations.
Figure 4.
 
Weibull survival analysis plot for age to legal blindness (i.e., visual acuity ≤ 20/200 or visual field equivalent diameter4 ≤ 20°), to visual acuity ≤ 20/200, and to visual field equivalent diameter ≤ 20° among patients with USH2A mutations. Vertical dashed lines: median ages for legal blindness.
Figure 4.
 
Weibull survival analysis plot for age to legal blindness (i.e., visual acuity ≤ 20/200 or visual field equivalent diameter4 ≤ 20°), to visual acuity ≤ 20/200, and to visual field equivalent diameter ≤ 20° among patients with USH2A mutations. Vertical dashed lines: median ages for legal blindness.
Figure 5.
 
Tomograms from a normal subject and from four patients (ages 54, 45, 43, and 52 years from top to bottom) with retinitis pigmentosa (RP) due to the Glu767fs mutation. Images span 6 mm horizontally. Arrow: low-reflectance outer nuclear layer (ONL) visible over the full 6 mm in the normal tomogram, in contrast to what is seen in the patient tomograms.
Figure 5.
 
Tomograms from a normal subject and from four patients (ages 54, 45, 43, and 52 years from top to bottom) with retinitis pigmentosa (RP) due to the Glu767fs mutation. Images span 6 mm horizontally. Arrow: low-reflectance outer nuclear layer (ONL) visible over the full 6 mm in the normal tomogram, in contrast to what is seen in the patient tomograms.
Table 1.
 
USH2A Mutations in DNA and Protein Format
Table 1.
 
USH2A Mutations in DNA and Protein Format
Exon/Intron Nucleotide Change Protein Change
3 c.545_546delAA Lys182fs
6 c.920_923dupGCCA His308fs
6 c.1026_29delCTCT Ser343fs*
6 c.1110_1111delTA Ile371fs
7 c.1214delA Asn405fs
7 c.1256G>T Cys419Phe
Intron 10 c.1841-2A>G Alters splice site IVS10-2A>G
11 c.1876C>T Arg626X
12 c.2073C>A Cys691X
12 c.2100delG Thr701fs*
Intron 12 c.2168-1G>C Alters splice site IVS12-1G>C
13 c.2276G>T Cys759Phe
13 c.2299delG Glu767fs
13 c.2761del C Leu921fs
16 c.3187_3188delCA Gln1063fs
20 c.4314delG Ile1439fs
20 c.4338_39delCT Cys1447fs
21 c.4510_4511insA Arg1504fs
22 c.4645C>T Arg1549X
26 c.5191_5192delAT Met1731fs
Intron 28 c.5775+1G>A Alters splice site IVS28+1G>A
Intron 29 c.5857+1G>C Alters splice site IVS29+1G>C
Intron 29 c.5857+2T>C Alters splice site IVS29+2T>C
30 c.5933_5940delCTGTTGTC Pro1978fs
32 c.6169C>T Gln2057X
40 c.7493delG Ser2498fs
41 c.8167C>T Arg2723X
42 c.8557A>T Arg2853X
44 c.8834G>A Trp2945X
48 c.9424G>T Gly3142X
52 c.10190_10191delAA Lys3397fs
59 c.11533C>T Gln3845X
61 c.11864G>A Trp3955X
Intron 61 c.12067-2A>G Alters splice site IVS61-2A>G
64 c.14010_14062del Glu4671fs
64 c.14131C>T Gln4711X
68 c.14803C>T Arg4935X
68 c.14879_c.14880delAAins45 Gln4960fs
Table 2.
 
Baseline Ocular Function of Patients with USH2A Mutations
Table 2.
 
Baseline Ocular Function of Patients with USH2A Mutations
ID Mutation (Exon) Mutation (Exon) Age (y) VA OD* VA OS* VF OD, † VF OS, † ERG OD, ‡ ERG OS, ‡
19238 Lys182fs (3) Glu767fs (13) 24 20/100 20/70 6,438 5,205 0.61 0.48
22085 His308fs (6) Trp3955X (61) 59 20/200 20/200 152 213 0.30 0.15
19083 His308fs (6) 15 20/30 20/30 10,451 8,768 1.89 1.82
06863 Ser343fs (6) 34 20/50 20/60 384 279 0.30 0.30
02933 Ile371fs (6) 31 20/30 20/40 1,073 585  NA  NA
19824 Asn405fs (7) 26 20/30 20/30 3,795 3,457 0.73 0.61
06236 Cys419Phe (7) 28 20/40 20/40 14,349 15,336 3.04 3.72
19477 Cys419Phe (7) IVS10-2A>G (I-10) 44 20/40 20/40 410 545 0.08 0.31
00304 Cys419Phe (7) 35 20/25 20/25 10,716 10,322 6.00 6.00
07018 Cys419Phe (7) 30 20/30 20/30 16,134 15,672 2.86 2.62
13287 Arg626X (11) Arg626X (11) 32 20/25 20/25 3,700 3,610 0.23 0.09
15597 Arg626X (11) Cys1447fs (20) 20 20/30 20/30 NA NA 2.31 1.75
13574 Cys691X (12) Glu767fs (13) 25 20/20 20/20 8,157 7,770 0.90 0.90
14419 Thr701fs (12) Gly3142X (48) 17 20/20 20/30 6,926 4,379 0.45 0.37
01376 IVS12-1G>C (I-12) 53 20/30 20/40 NA NA  NA  NA
05831 Cys759Phe (13) 43 20/40 20/50 1,576 1,646 0.26 0.24
13445 Cys759Phe (13) Trp3955X (61) 28 20/30 20/30 NA NA 29.40 29.40
15657 Cys759Phe (13) Cys759Phe (13) 36 20/25 20/50 10,920 9,497 9.24 4.20
11572 Cys759Phe (13) Cys759Phe (13) 15 20/30 20/30 7,711 9,867 0.41 0.55
05014 Cys759Phe (13) Cys759Phe (13) 35 20/40 20/30 9,132 8,980 22.00 22.00
06705 Cys759Phe (13) Glu767fs (13) 28 20/25 20/25 21,176 23,087 13.74 12.71
05918 Cys759Phe (13) Glu767fs (13) 40 20/30 20/30 8,367 8,174 7.48 9.13
06475 Cys759Phe (13) Glu767fs(13) 32 20/40 20/40 1,556 1,117 2.07 1.83
06792 Cys759Phe (13) Cys1447fs (20) 33 20/20 20/20 4,288 3,258 3.19 2.36
07889 Cys759Phe (13) Cys1447fs (20) 27 20/20 20/20 8,243 7,725 29.40 52.94
11439 Cys759Phe (13) Cys1447fs (20) 28 20/20 20/20 10,077 11,732 10.64 14.00
14338 Cys759Phe (13) Pro1978fs (30) 36 20/20 20/25 7,600 7,944 0.20 0.11
14436 Cys759Phe (13) IVS29+2T>C (I-29) 43 20/20 20/40 12,170 12,186 23.50 20.60
14483 Cys759Phe (13) 38 20/20 20/20 6,934 6,403 29.40 23.50
06966 Cys759Phe (13) 44 20/30 20/30 4,245 4,077 11.69 8.06
05666 Cys759Phe (13) 44 20/20 20/20 9,554 9,787 1.20 1.90
03458 Cys759Phe (13) Glu4671fs (64) 34 20/25 20/25 4,703 4,488  NA  NA
15221 Cys759Phe (13) 34 20/20 20/20 8,843 8,927 7.79 11.40
19431 Cys759Phe (13) 21 20/30 20/30 15,970 16,092 19.6 18.2
06191 Cys759Phe (13) 33 20/30 20/30 2,751 3,039 0.09 0.21
05917 Cys759Phe (13) 38 20/20 20/25 17,802 20,246 5.08 4.99
05907 Cys759Phe (13) 35 20/25 20/25 5,312 4,899 1.89 1.32
07008 Cys759Phe (13) 43 20/60 20/100 196 231 0.16 0.13
06898 Cys759Phe (13) 40 20/30 20/30 9,763 9,364 1.13 2.62
05967 Cys759Phe (13) 33 20/20 20/20 402 583 1.21 0.77
03753 Cys759Phe (13) 33 20/30 20/50 12,960 10,952 59.0 59.0
02874 Cys759Phe (13) 33 20/25 20/25 10,191 10,172 6.00 6.00
07065 Cys759Phe (13) 45 20/30 20/30 16,342 17,005 6.25 6.12
00220 Cys759Phe (13) 40 20/25 20/20 10,102 9,972  NA  NA
05377 Cys759Phe (13) 41 20/25 20/30 8,560 9,000 14.0 8.40
06144 Cys759Phe (13) 38 20/30 20/25 1,572 490 0.33 0.18
06210 Cys759Phe (13) 37 20/50 20/60 2,555 1,449 1.80 2.08
06732 Cys759Phe (13) 32 20/30 20/30 175 227 3.41 2.54
07879 Cys759Phe (13) 45 20/40 20/30 3,148 3,377 23.5 11.00
13613 Cys759Phe (13) 26 20/25 20/25 98 733 1.30 2.50
11259 Cys759Phe (13) 28 20/20 20/20 6,154 8,217 1.40 5.04
11505 Cys759Phe (13) 25 20/25 20/25 8,759 7,407 1.50 0.52
05011 Cys759Phe (13) 33 20/20 20/20 11,992 10,804 11.00 21.0
13115 Cys759Phe (13) 44 20/20 20/20 8,155 9,740 1.20 1.90
14027 Cys759Phe (13) 32 20/25 20/20 13,887 12,868 23.50 23.50
02726 Cys759Phe (13) 55 20/30 20/30 7,391 6,701 11.00 11.00
02943 Cys759Phe (13) 23 20/30 20/25 9,294 8,715  NA  NA
02954 Cys759Phe (13) 45 20/20 20/20 1,001 1,460  NA 12.0
00994 Cys759Phe (13) 36 20/40 20/50 366 264  NA  NA
15169 Glu767fs (13) 17 20/25 20/25 7,686 8,028 0.35 0.21
11451 Glu767fs (13) Gln4960fs (68) 27 20/20 20/20 9,997 10,274 1.19 1.40
22045 Glu767fs (13) Glu767fs (13) 27 20/50 20/50 6,141 4,992 1.87  NA
02265 Glu767fs (13) Cys1447fs (20) 17 20/25 20/50 5,415 5,654  NA  NA
02267 Glu767fs (13) Cys1447fs (20) 16 20/25 20/30 7,430 7,106  NA  NA
02266 Glu767fs (13) Cys1447fs (20) 15 20/20 20/20 10,467 9,806 62.0  NA
19249 Glu767fs (13) Arg1549X (22) 22 20/20 20/20 3,802 2,508 0.80 0.53
15499 Glu767fs (13) Arg2853X (42) 24 20/30 20/30 6,201 7,648 0.80 0.88
05958 Glu767fs (13) 37 20/30 20/30 12,011 12,341 8.00 8.00
11300 Glu767fs (13) IVS29+1G>C (I-29) 45 20/40 20/40 290 523 0.20 0.20
19281 Glu767fs (13) IVS61-2A>G (I-61) 44 20/25 20/20 3,329 1,618 2.35 1.91
06991 Glu767fs (13) 40 20/25 20/30 9,672 12,803 0.96 0.93
06724 Glu767fs (13) 31 20/40 20/40 12,591 11,592 1.10 0.92
05148 Glu767fs (13) 40 20/30 20/200 8,558 7,642 2.72 1.79
15297 Glu767fs (13) 45 20/60 20/25 11,342 10,503 5.87 4.56
15375 Glu767fs (13) 47 20/25 20/25 11,456 11,815 1.98 1.44
06704 Glu767fs (13) 24 20/30 20/40 10,999 7,670 35.9 34.2
06750 Glu767fs (13) 32 20/30 20/40 3,447 2,591 4.32 4.02
06178 Glu767fs (13) 36 20/40 20/25 650 881 0.56 0.48
06226 Glu767fs (13) 26 20/30 20/30 8,477 9,762 1.25 1.42
06256 Glu767fs (13) Arg1549X (22) 27 20/25 20/30 3,900 4,100 0.31 0.33
06650 Glu767fs (13) 33 20/20 20/25 13,164 11,544 1.62 1.81
06666 Glu767fs (13) 23 20/25 20/25 944 888 0.51 0.85
05751 Glu767fs (13) 23 20/30 20/20 5,306 5,518 0.32 0.47
06017 Glu767fs (13) 31 20/25 20/25 4,705 3,610 5.37 4.65
05916 Glu767fs (13) 39 20/25 20/30 4,140 5,787 1.96 1.96
03960 Glu767fs (13) 17 20/40 20/30 11,182 10,842 1.04 0.77
06798 Glu767fs (13) 32 20/25 20/25 14,005 15,158 2.05 1.38
05556 Glu767fs (13) 19 20/25 20/25 11,028 15,047 0.26 0.35
05213 Glu767fs (13) 15 20/20 20/20 7,774 8,778 1.05 1.08
02130 Glu767fs (13) 21 20/20 20/25 3,122 3,561 0.94 0.94
07031 Glu767fs (13) 26 20/30 20/40 14,551 13,448 1.15 0.77
02510 Glu767fs (13) 26 20/30 20/25 565 2,407 6.00 6.00
03193 Glu767fs (13) 28 20/20 20/20 638 690  NA  NA
05800 Glu767fs (13) 42 20/50 20/50 1,798 2,151 0.22 0.34
05785 Glu767fs (13) 27 20/30 20/25 14,130 17,982 3.52 3.07
07401 Glu767fs (13) 39 20/40 20/30 283 332 0.16 0.16
05252 Glu767fs (13) Arg4935X (68) 42  NA  NA 9,897 9,504  NA  NA
14015 Glu767fs (13) 25 20/20 20/20 9,755 10,317 17.60 20.60
01445 Glu767fs (13) 54 20/30 20/30 10,561 10,759 0.25 0.67
15938 Glu767fs (13) 29 20/30 20/40 7,220 7,556 0.74 0.60
15579 Glu767fs (13) 31 20/25 20/25 8,868 6,637 1.12 0.87
19822 Glu767fs (13) 52 20/40 20/60 168 138 0.14 0.11
05766 Leu921fs (13) Cys1447fs (20) 30 20/25 20/20 973 1,400 0.49 0.68
15285 Gln1063fs (16) Trp2945X (44) 22 20/25  NA 6,457 4,376  NA  NA
05960 Gln1408X (19) 33 20/25 20/25 3,974 5,820  NA  NA
07916 Ile1439fs (20) 30 20/20 20/20  NA  NA 0.50 0.70
04129 Cys1447fs (20) 6 20/40 20/30 10,261 11,787  NA  NA
04032 Cys1447fs (20) 7 20/40 20/30 4,839 4,754  NA  NA
03482 Cys1447fs (20) 19 20/30 20/30 10,576 11,651  NA  NA
06241 Cys1447fs (20) 36 20/30 20/30 13,131 7,372 11.96 12.59
07607 Cys1447fs (20) Arg4935X (68) 15 20/20 20/20 10,117 10,547  NA 1.40
11719 Cys1447fs (20) Cys1447fs (20) 27 20/25 20/25 9,121 9,317 1.10 1.10
06019 Cys1447fs (20) 40 20/50 20/50 489 421 0.10 0.12
06088 Arg1504fs (21) 20 20/25 20/25 1,572 1,410 0.20 0.30
03811 Arg1549X (22) 31 20/30 20/40 2,925 3,961  NA  NA
05857 Met1731fs (26) 39 20/70 20/100 14,753 14,331 3.14 2.50
07278 Gln2057X (32) 22 20/20 20/30 8,943 10,503 0.60 0.20
05558 Ser2498fs (40) 34 20/25 20/30 11,524 10,354 3.02 2.42
14888 Arg2723X (41) Arg2723X (41) 43 20/400 20/80 186 172 0.10  NA
00943 Arg2723X (41) 36 20/50 HM 234 198 0.17 0.10
03541 Gly3142X (48) 29 20/30 20/25 434 347  NA  NA
04132 Lys3397fs (52) IVS28+1G>A (I-28) 30 HM 20/50  NA 8,261  NA  NA
14402 Gln3845X (59) Gln3845X (59) 18 20/30 20/25 4,605 3,266 0.23 0.16
05765 Trp3955X (61) 24 20/30 20/50 110 129 0.29 0.33
14518 Gln4711X (64) 22 20/20 20/25 12,843 13,452 4.90 3.60
Arithmetic mean 31.6 20/28 20/29 7,003 6,987 5.91 5.50
Number of patients with values 125 124 123 120 121 105 104
Table 3.
 
Annual Rates of Change in Patients with USH2A Mutations
Table 3.
 
Annual Rates of Change in Patients with USH2A Mutations
Ocular Function n * Mean ± SEM (Geometric Mean), † P , †
Loge visual acuity 102 −0.026 ± 0.002 (−2.6%) <0.001
Loge visual field area 109 −0.074 ± 0.003 (−7.0%) <0.001
Loge ERG amplitude 69 −0.141 ± 0.005 (−13.2%) <0.001
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