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Novel USH2A Mutations in Israeli Patients with Retinitis Pigmentosa and Usher Syndrome Type 2

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Novel USH2A Mutations in Israeli Patients with Retinitis Pigmentosa and Usher Syndrome Type 2 OPHTHALMIC MOLECULAR GENETICS Novel USH2A Mutations in Israeli Patients With Retinitis Pigmentosa and Usher Syndrome Type 2 Nadia Kaiserman, MSc; Alexey Obolensky, MD, PhD; Eyal Banin, MD, PhD; Dror Sharon, PhD Objective: To identify USH2A mutations in Israeli pa- and a novel missense mutation (Gly4674Arg) had non- tients with autosomal-recessive Usher syndrome type 2 syndromic RP. (USH2) and retinitis pigmentosa (RP). Conclusions: Our results support the involvement of Methods: Patients from 95 families with RP and 4 with USH2A in nonsyndromic RP and we report here of a sec- USH2 were clinically evaluated. USH2A exons 2-72 were ond, novel, missense mutation in this gene causing au- scanned for mutations using single-strand conformation tosomal-recessive RP. and sequencing analyses. The frequency of novel mis- sense changes was determined in patients and controls Clinical Relevance: Possible involvement of USH2A using restriction endonucleases. should be considered in the molecular genetic evalua- Results: The analysis revealed 3 USH2A mutations, tion of patients with autosomal-recessive RP. Under- 2 of which are novel, in 2 families with USH2 and a standing the mechanism by which different USH2A mu- large family (MOL0051) with both USH2 and RP. Com- tations cause either USH2 or RP may assist in the pound heterozygotes for 2 null mutations (Thr80fs and development of novel therapeutic approaches. Arg737stop) in MOL0051 suffered from USH2 while compound heterozygotes for 1 of the null mutations Arch Ophthalmol. 2007;125:219-224 ETINITIS PIGMENTOSA (RP) expressed in additional tissues as well. is a group of progressive Recent studies suggest that usherin is rod-cone degenerations integrated into a protein network formed characterized by night by other USH-causing proteins.8,9 USH2A blindness followed by can produce a short isoform (encoded by visual-field loss, resulting in severe visual exons 2-21) and long isoforms produced R 10 impairment. Most patients have no asso- by alternative splicing of exons 2-72. ciated systemic disease (nonsyndromic More than 50 pathogenic mutations have 11-19 RP) while others suffer from associated been reported so far in exons 2-21 and 5 mutations were reported in exons extraocular diseases. The most common 10 syndromic RP is Usher syndrome, with 22-72. Interestingly, 1 missense muta- an estimated prevalence of 5:100 000 live tion, Cys759Phe, is responsible for births.1 Usher syndrome can be catego- approximately 7% of nonsyndromic rized into 3 clinical types: patients with autosomal-recessive RP (ARRP) cases, suggesting that under certain conditions Usher type 1 (USH1) typically have con- USH2A can cause RP without hearing genital deafness, vestibular ataxia, and loss.14,18 We report here the identification night blindness noted in the first or sec- of novel USH2A mutations causing USH2 ond decade, whereas in USH2, night and nonsyndromic RP in the Israeli blindness appears in the second to fourth population. decade, accompanied by moderate early- onset hearing loss and no ataxia.2,3 Usher type 3 is found mostly among Finnish patients with onset of progressive hear- METHODS ing loss and RP in the late teens and vari- able vestibular dysfunction.4 At least 3 genetic USH2 loci were Index patients from 95 Jewish and Muslim Is- identified with USH2A being the most raeli families with ARRP and 4 with USH2 were Author Affiliations: recruited for this study. All patients under- Department of Ophthalmology, common, responsible for approximately went clinical evaluation that included full oph- 5,6 Hadassah-Hebrew University 85% of USH2 cases. USH2A encodes thalmologic examination, assessment of re- Medical Center, for usherin, a basement membrane pro- fractive error, visual field testing, color vision Jerusalem, Israel. tein in the inner ear and retina,7 and is testing, and full-field electroretinography (REPRINTED) ARCH OPHTHALMOL / VOL 125, FEB 2007 WWW.ARCHOPHTHALMOL.COM 219 ©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 A MOL0051 12 I 1234567891011121314 II 123456789 10 11 12 13 14 15 16 17 18 19 III 7 7 3 4 9 4 B MOL0051 MOL0165 MOL0035 12 1 2 12 78 I I II – – + – T80fs 1 1 1 2 A125T 2 2 2 1 T473T 1 1 1 2 IVS9+33 + – – – R373X 1234 12 34 – – – + R4674G II II R373X/ T80fs/ 4569 10 12 R373X + III – + – + – – – + – – + – 1 1 1 1 1 2 1 1 2 2 1 2 2 2 2 2 2 1 2 2 1 1 2 1 1 1 1 1 1 2 1 1 1 2 1 2 + – + – + – + – – – – – – – – – – + – – – + – + Figure 1. Israeli families with USH2A mutations. A, Family MOL0051. B, Single nucleotide polymorphisms and USH2A mutations in 3 Israeli families. Gray filling denotes retinitis pigmentosa and black filling denotes Usher syndrome type 2. Numbers above symbols indicate recruited individuals and numbers within diamonds indicate the number of siblings. A slash over an individual symbol indicates that person is deceased. (ERG). All patients had typical RP changes to varying degrees (MOL0051) was the focus of the study, presenting a com- and full-field ERG confirmed various levels of rod more than plex inheritance pattern in which some family members cone dysfunction. Patients with USH2 reported partial hear- suffered from USH2 while others had nonsyndromic RP ing loss, which was tested clinically and verified by audiom- (Figure 1A). MOL0051 is of Iraqi Jewish origin with etry when required. Patients with nonsyndromic ARRP were no clear pattern of disease inheritance, but consanguin- asked about hearing problems and additional testing was per- formed if hearing impairment was suspected. The tenets of the ity in some branches of the family would suggest an au- Declaration of Helsinki were followed and informed consent tosomal-recessive inheritance. In the nuclear family, the was obtained from all patients who participated in this study mother (II-2) has 1 brother with USH2 and 3 siblings with prior to donation of a blood sample. RP. Three of her children manifest USH2 while 3 others The single-strand conformation polymorphism technique were diagnosed with RP (Figure 1A). At the age of 66 was used to screen genomic DNA for mutations in exons 2-21 years, she had advanced RP, including nonrecordable ERG and to perform haplotype analysis using single nucleotide poly- responses and severely constricted visual fields morphisms. Mutation analysis of exons 22-72 was done by se- (Figure 2A and B), while her audiometry findings were quencing of polymerase chain reaction products (primer se- normal. Her 3 daughters with RP (aged 32-39 years) had quences are available on request). The frequencies of missense changes were tested in 94 ARRP index cases and 10 unrelated somewhat less severe retinal disease, but all were legally controls using restriction enzymes (MboII for C759F, Hpy188I blind, as shown in the representative clinical data of pa- for I1665T, TspRI for R2875Q, BtsI for N3099S, BfuCI and tient III-6 (Figure 2A and C). The youngest son (III-9) Sau3AI for D3144N, NdeI for I3335M, FokI and HpaII for with USH2 still had residual cone responses on ERG, but R4674G). In 2 sequence changes (I1665T and R4674G), where in his 2 older siblings with USH2, ERGs were nonrecord- no restriction enzyme could distinguish between the wild- able (Figure 2A). All 3 were found to have mild to mod- type and the mutant alleles, we designed a primer located ad- erate hearing loss in early childhood (a representative au- jacent to the sequence change and included a base change in diogram of patient III-4 at the age of 38 years is shown the primer sequence to create a restriction site. in Figure 2E). The visual field findings as well as fundus photograph and autofluorescence image for this patient RESULTS are shown in Figure 2D, F, and G (note residual ring of hyperfluorescence in macular area surrounded by large We studied the involvement of USH2A in 44 families with patches of hypofluorescence corresponding to areas of ARRP and 4 families with USH2. One of these families atrophy). (REPRINTED) ARCH OPHTHALMOL / VOL 125, FEB 2007 WWW.ARCHOPHTHALMOL.COM 220 ©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 A Pt No. Diagnosis Age, y VA (OD OS) Cone Flicker Mixed ERG Rod ERG EOG Arden Color Vision ERG, µV, ms a, b Waves, µV b Wave, µV Ratio, % III-6 RP 34 6/6 24, 39 29, 40 Extinct 139 Normal 6/7.5 11, 39 17, 50 139 II-2 RP 66 6/27 Extinct Extinct Extinct 100 Tritanopia 6/54 100 III-9 USH2 28 6/15 20, 42 Extinct Extinct 162 Normal 6/15 20, 44 160 III-5 USH2 36 6/18 Extinct Extinct Extinct 106 Normal 6/15 114 III-4 USH2 38 6/15 Extinct Extinct Extinct 111 Tritanopia 6/15 100 Normal Values 6/6 >60, <33 a>100 >200 >185 b>400 120 105 90 75 60 120 105 90 75 60 B C 135 70 45 135 70 45 60 60 150 50 30 150 50 30 40 40 30 30 165 15 165 15 20 20 10 10 90 80 70 60 50 40 30 20 10 10 20 30 40 50 60 70 80 90 90 80 70 60 50 40 30 20 10 10 20 30 40 50 60 70 80 90 10 10 20 195 195 20 30 345 30 345 40 40 210 50 330 210 50 330 60 60 225 70 315 225 70 315 240255 270 285 300 Pt II-2240255 270 285 300 Pt III-6 120 105 90 75 60 D E –10 135 70 45 60 0 150 50 30 10 40 20 30 165 15 20 30 10 40 90 80 70 60 50 40 30 20 10 10 20 30 40 50 60 70 80 90 50 dB 10 60 195 20 30 345 70 40 80 210 50 330 90 60 100 225 70 315 110 240255 270 285 300 Pt III-4 250 500 1000 2000 4000 8000 Hz F G Figure 2.
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