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Phenotype of Autosomal Dominant Cone–Rod Dystrophy Due to the R838C Mutation of the GUCY2D Gene Encoding Retinal Guanylate

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Phenotype of Autosomal Dominant Cone–Rod Dystrophy Due to the R838C Mutation of the GUCY2D Gene Encoding Retinal Guanylate Eye (2007) 21, 1220–1225 & 2007 Nature Publishing Group All rights reserved 0950-222X/07 $30.00 www.nature.com/eye 1 2 3 3 CASE SERIES Phenotype of M Smith , N Whittock , A Searle , M Croft , C Brewer3 and M Cole1 autosomal dominant cone–rod dystrophy due to the R838C mutation of the GUCY2D gene encoding retinal guanylate cyclase-1 Abstract should therapeutic interventions become available. Aims: To describe the phenotype of members Eye (2007) 21, 1220–1225; doi:10.1038/sj.eye.6702612; of a large Caucasian British family affected by published online 13 October 2006 autosomal dominant cone–rod dystrophy due to an R838C mutation in the guanylate cyclase Keywords: cone dystrophy; cone–rod dystrophy; 2D (GUCY2D) gene encoding retinal guanylate GUCY2D; RETGC-1 cyclase-1 (RETGC-1). Methods: Retrospective review of 29 patients from four generations of the same family. Results: Visual symptoms usually commenced Introduction in childhood. Only two patients, aged 14 and 1 Cone dystrophies are a genetically Department of 25 years, had visual acuity compatible with Ophthalmology, Torbay heterogeneous group of disorders characterised driving. Of the 12 patients aged over 40 years, Hospital, Torquay, by early deterioration of visual acuity and eight (66%) had vision of counting fingers or Devon, UK colour vision.1 Although cone dystrophies with worse and were eligible for blind registration normal rod function may occur, in most cases 2Institute of Biomedical and in the UK. Of the 29 patients, 18 (62%) had there is a degree of rod impairment, albeit less Clinical Science, Peninsula myopia greater than 5 D in at least one eye. Medical School, Exeter, UK severe than that of cone function and often not Most had discernible macular changes on evident until late in the disease. These patients biomicroscopy, which varied from subtle RPE 3Department of Clinical are described as having cone–rod dystrophies. change to gross macular atrophy. All patients Genetics, Royal Devon and Cone and cone–rod dystrophy are genetically Exeter Hospital, Exeter, UK who underwent computerised perimetry heterogeneous with dominant, recessive, and exhibited a central or paracentral scotoma with X-linked inheritance patterns described. To Correspondence: M Smith, normal peripheral field of vision. Of the Department of date, nine loci for autosomal dominant cone and 21 patients who underwent electrodiagnostic Ophthalmology, Torbay cone–rod dystrophies have been identified: Hospital, Lawes Bridge, testing, all exhibited decreased cone function, CORD4, RCD1, AIPL1, CRX, GUCA1A, Torquay, Devon but rod function was normal in 12 (57%) GUCY2D, RIMS, UNC119, and SEMA4A. TQ2 7AA, UK patients. In 1997, Kelsell et al2 localised a gene Tel: þ 01803 614567; Conclusion: We believe this report highlights Fax: þ 01803 616334. responsible for autosomal dominant cone–rod E-mail: SMITH@ the importance of phenotype–genotype dystrophy (ADCRD) in a British family mic73.freeserve.co.uk correlation in cone and cone–rod dystrophies. (CORD6) to chromosome 17p. Further work Increased understanding of the varying revealed mutations in the guanylate cyclase 2D Received: 21 December phenotypes associated with different genetic (GUCY2D) gene encoding retinal guanylate 2005 mutations allows appropriate counselling cyclase-1 (RETGC-1) to be responsible.3,4 Accepted in revised form: of patients. In addition, the phenotypic 12 September 2006 Analysis of the original CORD6 family and characterisation of the natural history of these other families with ADCRD identified single Proprietary interests: Nil conditions may prove valuable in the future or multiple mutations in codons 837, 838, or 839 Autosomal dominant cone–rod dystrophy M Smith et al 1221 of the GUCY2D gene.4–7 The phenotypes of these families D6S1549), GUCY2D on 17p (D17S1353, D17S960, appears to vary depending on the specific mutation and D17S786, D17S1796), and the CRX gene on 19q13.3 the presence or absence of multiple mutations. There is (D19S902, D19S604) were amplified in a mix containing also some phenotype variation both between and within 40 ng genomic DNA, 5 pmol of forward and reverse families with the same mutation. primers, 2.5 nmol each dNTP, 100 mM Tris-HCl, 500 mM A large Caucasian family of British origin with KCl, 15 mM MgCl2, and 0.25 U Amplitaq Gold Taq ADCRD due to an arginine to cysteine missense polymerase (Applied Biosystems). Forward or reverse mutation at amino-acid residue 838 (R838C) has been primers were labelled with 6-FAM or HEX fluorescent attending our department for many years. This paper dyes. Reaction conditions were initial denaturation of describes the phenotype of 29 affected members of this 951C for 12 min, followed by 10 cycles of 941C for 30 s, family. 551C for 30 s, 721C for 1 min, and then 30 cycles of 891C for 30 s, 551C for 30 s, and 721C for 1 min, with a final step 1 Materials and methods of 72 C for 7 min. PCR products were separated by polyacryamide gel electrophoresis on an ABI 377 DNA Patients sequencer and analysed using Genescan 3.0 and A pedigree of this family identified 35 members with Genotyper 2.5 software (Applied Biosystems). Primers likely cone–rod dystrophy. Of the 35 family members, 29 sequences were obtained from the Genome Database were current patients in our department or had attended (http://www.gdb.org/). Tails to reduce stutter bands 0 within the last 5 years. The case notes of all 29 were (GTTTCTT) were introduced to the 5 end of either the reviewed. Of the 29 patients, nine had undergone forward or reverse primer. molecular genetic investigation. Identification of mutations in the GUCY2D gene Exon 13 of the human GUCY2D gene was directly Clinical and functional investigations amplified from genomic DNA using primers GUCY2D All 29 patients had undergone clinical examination 13F (50-GTA GAT GAA TGG TGG CAG CG-30) and including Snellen visual acuity and dilated retinal GUCY2D 13R (50-GAT GGC AGG CAG TGA GGT C-30). examination. A total of 18 patients had undergone colour Intronic primers were designed based on the genomic vision testing using Ishihara pseudo-isochromatic plates sequence of GUCY2D (http://genome.ucsc.edu/). and 13 patients static threshold perimetry using the Approximately 200 ng of patient or control genomic standard 24-2 threshold protocol on the Humphrey Field DNA was used in a 50 ml reaction mixture containing Analyser. A total of 21 patients had undergone 20 pmol forward and reverse primers, 10 nmol each of electrodiagnostic investigation. dTTP, dCTP, and dATP, 7.6 nmol dGTP, 2.5 nmol deaza GTP, 2.5 ml DMSO, 50 mmol betaine, 100 mM Tris-HCl, 500 mM KCl, 15 mM MgCl , and 1.0 U Amplitaq Gold Genotyping 2 Taq polymerase (Applied Biosystems). After an initial Nine of the 29 patients and one unaffected family denaturation of 951C for 12 min, 40 cycles were member had undergone molecular genetic investigation. performed of 951C for 1 min, 551C for 1 min, and 721C for 2 min, with a final extension step of 721C for 10 min. Haplotype analysis The PCR products were examined by 2% agarose gel Microsatellite markers proximal and distal to the RDS electrophoresis, purified using spin columns (Qiagen, gene on 6p (D6S1582, D6S1552, D6S1017, D6S1672, Crawley, England) and directly sequenced using Big I1 I2 II1 II2 II3 II4 II5 II6 II7 II8 II9 II10 III1 III2 III3 III4 III5 III6 III7 III8 III9 III10 III11 III12 III13 III14 III15 III16 III17 III18 III19 III20 IV1 IV2 IV3 IV4 IV5 IV6 IV7 IV8 IV9 IV10 IV11IV12 IV13 IV14 IV15 IV16 IV17 IV18 IV19 IV20 V1 V2 V3 V4 V5 V6 V7 V8 V9 V10 Figure 1 Pedigree of family with autosomal dominant cone dystrophy. Roman numerals indicate generations; solid symbols, affected family members; open symbols, unaffected family members; squares, males; circles, females; slash, deceased. Eye Eye 1222 Table 1 Clinical characteristics and electrophysiological results Rod-specific Single flash 30 Hz flicker cone Decade of ERG (b-wave) cone ERG (b-wave) ERG (b-wave) Pedigree Age symptom no. (years) Sex onset VA OD VA OS Refraction OD Refraction OS Fundus LAT AMP LAT AMP LAT AMP Autosomal dominant cone–rod dystrophy II-8 78 M 1 CF CF À6.00/À2.50 À5.50/À1.50 3 Not performed FF F F F II-9 80 F 1 CF CF À2.00 À2.00 2 Not performed FF F F F III-3 57 M 1 CF CF þ 1.00/ þ 1.25 þ 1.00/ þ 0.75 3 Not performed FF F F F III-8 56 M 3 CF 6/24 À6.75 À6.50/À2.00 1 N N mkmk III-10 48 M 1 6/60 6/60 À3.00/À2.00 À2.50/À1.50 2 N N N N mk III-12 61 F 1 CF CF À11.00/À2.00 À15.00/À2.50 3 mkmkmk III-13 60 F 1 HM HM À4.50/À3.00 À5.00/À3.50 3 Not performed FF F F F k k III-16 51 M 2 6/60 6/60 À0.25 þ 0.25/ þ 0.25 3 N N N N M Smith III-18 53 M 1 CF CF À10.00/À2.00 À10.00 3 Not performed FF F F F III-19 66 F 1 CF CF À8 À8.5 3 N N ABS ABS ABS ABS III-20 55 M 1 CF CF À6.00/À2.50 À6.00/À2.00 3 Not performed FF F F F et al IV-1 38 F 1 6/36 6/60 À7.00/À1.00 À9.00/À2.25 1 N N mkmk IV-3 38 M 3 6/60 6/60 þ 1.5 þ 2.25/À1.50 2 mkABS ABS ABS ABS IV-5 22 M 1 6/36 6/18 À5.50/À3.5 À3.75/À4.5 0 N k N kmk IV-6 25 F 2 6/6 6/6 þ 1.00/À2.50 À0.50/À1.50 1 N N N k N k IV-7 21 F 1 6/18 6/18 þ 0.75/À1.50 þ 0.25/À1.50 1 Not performed FF F F F IV-8 28 M 1 CF CF À6.00/À1.00 À5.50/À1.00 0 mkABS ABS ABS ABS IV-11 32 F 1 6/36 6/24 À3.75/À0.75 À3.25/À0.75 1 N N mkmk IV-12 30 M 3 6/12 6/12 À1.00/À1.25 À0.75/À1.25 1 mkmkmk IV-14 12 M 1 6/36 6/36 þ 3.75/À5.00 þ 3.75/À3.50 1 N N N kmk IV-15 34 F 1 6/36 6/36 À10.75/ þ 0.50 À13.25/ þ 4.25 2 N N N N mk IV-16 41 M 1 6/18 6/18 À6.50/ þ 1.50 À7.00/ þ 1.25 1 Not performed FF F F F IV-17 32 M 1 6/24 6/18 À9.50/À0.50 À8.50/À1.00 0 mkmkmk IV-19 40 M 3 6/60 6/60 À8.25 À9.00/ þ 0.50 2 mkmkmk IV-20 32 M 3 CF CF À1.75/À3.00 À2.00/À4.00 2 N k N k ABS ABS V-1 17 F 2 6/18 6/24 À7.00/À2.00 À1.75/À2.00 2 N N mkmk V-2 14 M 1 6/18 6/60 À4.50/À2.00 À4.50/À2.00 1 N N mkmk V-4 14 M 1 6/36 6/9 À6.00/À1.75 À4.25/À1.00 1 N N N k N k V-10 19 F 1 6/18 6/18 À7.25/À3.50 À8.75/À5.25 1 mkmkmk ERG ¼ electroretinogram; LAT ¼ latency; AMP ¼ amplitude; N ¼ normal; m ¼ increased; k ¼ decreased; ABS ¼ absent.
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