Novel Complex GUCY2D Mutation in Japanese Family with Cone-Rod Dystrophy

Sei Ito,1 Makoto Nakamura,1 Yoshihisa Nuno,2 Yoshitaka Ohnishi,3 Teruo Nishida,2 and Yozo Miyake1

PURPOSE. All mutations in the retinal guanylate cyclase gene disturbances. The electrophysiological results are a greater (GUCY2D) that causes autosomal dominant cone-rod dystro- reduction of the cone electroretinograms (ERGs) than the rod phy (CORD) are associated with an amino acid substitution in ERGs. In patients with cone dystrophy (COD), cone function is codon 838. A novel heterozygous complex missense mutation depressed progressively but rod function is well preserved of I915T and G917R in the GUCY2D gene was found in a until the late stages. Japanese family with autosomal dominant CORD. The clinical Cone-rod dystrophy is genetically heterogeneous, and ac- features associated with this mutation were described. cording to RETNET (http://www.sph.uth.tmc.edu/retnet/ METHODS. Blood samples were collected from 27 patients with home.htm), nine genes have been identified to cause CORD or COD: CRX,1,2 GUCY2D,3 AIPL1,4 GUCA1A,5 RIMS1,6 and cone-rod or cone dystrophies and from 11 patients with mac- 7 ular dystrophy. Genomic DNA was extracted from peripheral UNC119 are causative genes for autosomal dominant CORD; ABCA48 and RDH59 are causative genes of autosomal recessive leukocytes. All 18 coding exons of the GUCY2D gene were 10 directly sequenced. The PCR product carrying a novel muta- CORD; and RPGR is a causative gene of X-linked recessive tion was subcloned, and each allele was sequenced. A com- CORD. Also, six loci of the CORD-causing genes have been plete ophthalmologic examination was performed in members mapped; RCD1 on 6q25-q26, COD2 on Xq27, CORD4 on 17q, of the family with the novel mutation. CORD5 on 17p13-p12, CORD8 on 1q12-q24, and CORD9 on 8p11. RESULTS. A novel heterozygous complex missense mutation of The GUCY2D gene encodes human photoreceptor-specific T2817C and G2822C that would predict I915T and G917R guanylate cyclase (RetGC-1) which catalyzes the conversion of amino acid substitutions, respectively, was found in an auto- guanosine triphosphate (GTP) to cyclic 3Ј,5Ј-guanosine mono- somal dominant CORD family. The two nucleotide changes phosphate (cGMP) in mammalian photoreceptor cells.11 The were located on the same allele, and segregated with the gene was first proved to be responsible for autosomal recessive disease. Two other known missense mutations of R838H and Leber congenital amaurosis (LCA) as a homozygous or a com- R838C were found in two other CORD families. The clinical pound heterozygous mutation.12 phenotype associated with the novel mutation was similar to In 1998, a heterozygous mutation of the GUCY2D gene was that with the Arg838 mutations. found to cause another ocular phenotype. Thus, a heterozy- CONCLUSIONS. A heterozygous complex mutation of I915T and gous complex mutation of E837D and R838S was identified in G917R in the GUCY2D gene caused autosomal dominant a large British family with autosomal dominant CORD CORD, indicating that a heterozygous mutation that does not (CORD6).3,13 Subsequently, three additional heterozygous mu- include a codon 838 substitution can lead to this ocular tations in the GUCY2D gene in ten unrelated European families phenotype. (Invest Ophthalmol Vis Sci. 2004;45:1480–1485) with CORD have been reported; R838C in six families,3,14,15 DOI:10.1167/iovs.03-0315 R838H in two families,14,16 and a triple mutation of E837D ϩ R838C ϩ T839M in one family.17 All of these mutations causing one-rod dystrophy (CORD) is a subgroup of inherited CORD are in the same or in adjacent codons including codon Cchorioretinal dystrophies that is associated with progres- 838, and are located in the putative dimerization domain of the sive impairment of central vision and a central scotoma with RetGC-1 protein.18 atrophic retinal changes in the macula. The typical symptoms A novel heterozygous complex missense mutation, T to C at at onset include loss of color discrimination and central visual nucleotide 2817 predicting an I915T amino acid substitution, andaGtoCatnucleotide 2822 predicting a G917R amino acid substitution was analyzed. This mutation was found in a family From the 1Department of Ophthalmology, Nagoya University with autosomal dominant CORD. Their clinical phenotypes Graduate School of Medicine, Nagoya, Japan; the 2Department of indicated that a heterozygous mutation not involving codon Biomolecular Recognition and Ophthalmology, Yamaguchi University 838 can cause an ocular phenotype of autosomal dominant School of Medicine, Ube, Japan, and the 3Department of Ophthalmol- CORD. ogy, Wakayama Medical University, Wakayama, Japan. Supported by grants for Research Committee on Chorioretinal Degenerations from The Ministry of Health and Welfare, Grants-in-Aid PATIENTS AND METHODS for Scientific Research B14370556 (MN), and A13307048 (YM) from The Ministry of Education, Science, Sports and Culture, Japan. Subjects Submitted for publication March 27, 2003; revised July 16 and October 18, 2003; accepted October 22, 2003. Based on ERG examinations, 27 families that had CORD or COD and 11 Disclosure: S. Ito, None; M. Nakamura, None; Y. Nuno, None; families with macular dystrophy (MD) were chosen for this study. Nine Y. Ohnishi, None; T. Nishida, None; Y. Miyake, None families with CORD or COD and one family with MD showed an The publication costs of this article were defrayed in part by page autosomal dominant inheritance pattern. To the best of our knowl- charge payment. This article must therefore be marked “advertise- ment” in accordance with 18 U.S.C. §1734 solely to indicate this fact. edge, the families were not related. Corresponding author: Makoto Nakamura, Department of Oph- In family #65 with a novel complex mutation, 6 affected members thalmology, Nagoya University Graduate School of Medicine, 65 Tsu- and 4 unaffected members were used for a segregation study and ruma-cho, Showa-ku, Nagoya 466-8550, Japan; clinical examinations (Fig. 1). Other members of the family would not [email protected]. consent to participate in this study.

Downloaded from jov.arvojournals.org on 10/01/2021 IOVS, May 2004, Vol. 45, No. 5 Novel Double GUCY2D Mutation in CORD Family 1481

the two missense sequence changes were considered to be located on the same allele. We further confirmed the segregation of the mutation by SSCP analysis using the PCR products of exon 14 of the GUCY2D from all available family members. Affected individuals with the I915T and G917R mutations showed an excess band due to possible unusual homoduplex or heteroduplex molecules on the gel, which were present neither in unaffected individuals nor in a normal control (data not shown). Two other heterozygous mutations in two other autosomal dominant CORD families were identified from this screening; a FIGURE 1. Pedigrees of a family (#65) with autosomal dominant cone- missense mutation of G to A at nucleotide 2586, predicting an rod dystrophy caused by novel GUCY2D mutations showing affected R838H amino acid substitution, and a missense mutation of C (solid symbols) and unaffected (open symbols) members. Family num- to T at nucleotide 2585, predicting an R838C amino acid bers and patient numbers correspond to those in text, Figures 3, 4, and substitution (Table 1). These two mutations were the same as 5. An arrow points to the proband. Individuals whose DNA were those reported in white people,3,14–16 indicating that codon tested are indicated by X. Squares, males; circles, females; slash 838 is a focus for autosomal dominant CORD internationally. through symbol, deceased. The detailed clinical features of the families with the codon 838 mutations will be described elsewhere. Eleven other sequence variants were noted, and five were This study was conducted in compliance with tenets of the Decla- predicted to cause amino acid changes. However, whether ration of Helsinki, and informed consent was obtained from the sub- they were disease-causing mutations could not be determined. jects after an explanation of the purpose and procedures of this study. All mutations and polymorphisms found are listed in Table 1. A The ophthalmologic examination included best-corrected visual acuity, heterozygous T134C sequence change (W21R) was found in a refraction, biomicroscopy, ophthalmoscopy, fundus photography, female patient and was not present in 100 normal control Goldmann kinetic perimetry, and ERG. Color visual testing was per- alleles. This mutation was believed not to be disease-causing formed with panel D-15 and Ishihara plates. but a rare polymorphism because the patient’s father had the Direct Sequencing sequence change homozygously without any ocular abnormality. Genomic DNA was extracted from peripheral blood leukocytes. All 18 A heterozygous G1697A sequence change (G542S) was coding exons of the GUCY2D gene were amplified by polymerase found in a male proband but not in 100 normal control alleles. chain reaction (PCR) and directly sequenced as described.19 Primers However, whether it was a disease-causing mutation or a rare were purchased from Life Technologies Oriental, Inc. (Tokyo, Japan) polymorphism could not be determined, because no other using published sequences.3,12 To search for polymorphisms, exons family members were available for a segregation study. 2a, 3, 4, 7, 10, 11, 13, and 14 of the GUCY2D gene from 100 alleles (26 A G227T (A52S) sequence change was found in 31 pro- men and 24 women) from unrelated normal Japanese individuals were bands, homozygously in 13, and heterozygously in 18. How- directly sequenced. ever, it was also detected in normal control individuals homozygously in 25 and heterozygously in 23, and was Subcloning of GUCY2D Alleles considered to be a polymorphism. The PCR product of exon 14 of the GUCY2D in patient IV-7, the A C2174T (P701S) variant, that was found in 17 probands, proband of family #65, was cloned into pCR2.1-TOPO vector using homozygously in 2 and heterozygously in 15, was also consid- TOPO TA Cloning Kits (Invitrogen, Carlsbad, CA), and ten clones were ered to be unrelated to the disease because it was detected in sequenced using the same primers for the direct genomic sequencing. 19 normal control individuals heterozygously. A C237T (T55M) sequence change was found in 3 healthy individuals heterozygously, but was not found in patients. RESULTS Three heterozygous silent mutations, C154T (P27P), G2167A (P698P), and C2257T (D728D), were detected in only Genetic Analysis one proband and were not found in control alleles. Another The screening of GUCY2D in 38 patients with CORD, COD, or silent mutation, G2575A (L834L), was found heterozygously in MD revealed three disease-causing mutations in three separate two normal control individuals but not in patients. Two other Japanese families with autosomal dominant CORD. In one silent mutations, C814T (H247H) and C1444T (C457C), were family (#65; Fig. 1), novel double heterozygous sequence identified in both patients and controls (Table 1). changes were detected in the proband (IV-7). The changes ؉ were T to C transition at nucleotide 2817 and G to C transition Phenotype of Family #65 (I915T G917R) at nucleotide 2822 in exon 14, resulting in missense substitu- Family #65 with CORD showed a typical autosomal dominant tions of threonine for isoleucine in codon 915 and arginine for hereditary pattern through four generations (Fig. 1). The male glycine in codon 917, respectively (Fig. 2A). Direct genomic proband (IV-7) who first noticed a reduction of visual acuity at DNA sequencing of the GUCY2D gene in the other 9 available approximately 20 years of age was referred to our hospital at members of the family showed that all 5 affected members had age of 25 years. His best-corrected visual acuity was 0.1 in the both heterozygous sequence changes, and none of the unaf- right eye and 0.09 in the left eye with severe myopic refractive fected members had either of the two sequence changes. errors of approximately Ϫ10 diopters in each eye. He failed all These results led to the suspicion that the novel double of the Ishihara color plates, and the panel D-15 test revealed sequence changes would be located on the same allele. To tritanomaly. confirm this, the PCR product of exon 14 of the gene from the Fundus examination showed only minimal disruption with proband (IV-7) was cloned into a pCR2.1-TOPO vector and tiny yellow deposits in the fovea (Fig. 3E), and fluorescein the sequences of each allele were determined. Six out of ten angiography showed no apparent abnormality (Fig. 3F). No clones had both sequence changes (Fig. 2C), whereas the visual field defect was detected by Goldmann kinetic perimetry remaining four showed the wild-type sequence (Fig. 2B). Thus, in both eyes (Fig. 4C).

Downloaded from jov.arvojournals.org on 10/01/2021 1482 Ito et al. IOVS, May 2004, Vol. 45, No. 5

FIGURE 2. (A) Nucleotide sequences of GUCY2D using sense primers in the patients of the family (#65). Two closely-located heterozygotic missense mutations of T to C at nucleotide 2817 (I915T) and G to C at nucleotide 2822 (G917R) were found in exon 14. (B) An allele of exon 14 of the gene from the proband (IV-7) was the wild type without either mutation. (C) Another allele of exon 14 of the gene from the proband (IV-7) carried both mutations of I915T and G917R showing that the two missense sequence changes were located on the same allele. (D) Amino acid sequence alignment of human RetGC-1, human RetGC-2,25 rat GC-E, GC-F26 and bovine ROS-GC.27 Aster- isks identify residues of identity, and residues Ile915, which is replaced by Thr, and Gly917 which is replaced by Arg are indicated by arrows.

TABLE 1. Mutations and Polymorphisms in the GUCY2D Gene

Allele Frequency (%) Amino Nucleotide Acid CORD Normal Type of Exon Variant* Change Probands Controls Mutation

2 134T3C W21R 1/76 (1.3) 0/100 Polymorphism 2 154C3T P27P 1/76 (1.3) 0/100 Polymorphism 2 227G3T A52S 44/76 (58) 73/100 (73) Polymorphism 2 237C3T T55M 0/76 3/100 (3.0) Polymorphism 3 814C3T H247H 20/76 (26) 15/100 (15) Polymorphism 4 1444C3T C457C 6/76 (7.9) 11/100 (11) Polymorphism 7 1697G3A G542S 1/76 (1.3) 0/100 Polymorphism or missense† 10 2167G3A P698P 1/76 (1.3) 0/100 Polymorphism 10 2174C3T P701S 19/76 (25) 19/100 (19) Polymorphism 11 2257C3T D728D 1/76 (1.3) 0/100 Polymorphism 13 2575G3A L834L 0/76 2/100 (2.0) Polymorphism 13 2585C3T R838C 1/76 (1.3) 0/100 Missense 13 2586G3A R838H 1/76 (1.3) 0/100 Missense 14 2817T3C ϩ I915T ϩ 1/76 (1.3) 0/100 Missense ϩ 2822G3C G917R missense

* Nucleotides numbered from the ATG initiator codon based on a cDNA reference (GenBank M92432). † Not determined because a segregation analysis could not be performed.

Downloaded from jov.arvojournals.org on 10/01/2021 IOVS, May 2004, Vol. 45, No. 5 Novel Double GUCY2D Mutation in CORD Family 1483

refractive errors were either mild myopia or hyperopia in all of the affected and unaffected family members except for the high myopic proband (IV-7) and an unaffected man (IV-6) who had moderate myopia of approximately Ϫ5.0 diopters. Astig- matism was not high in all subjects. Full-field ERGs recorded from the proband (IV-7) according to the ISCEV protocol showed that the photopic and 30 Hz flicker ERGs were almost nonrecordable, and that the ampli- tude of scotopic b-wave was subnormal. In the bright-flash mixed rod-cone ERG, the a- and b-waves as well as the oscillatory potentials (OPs) were within the normal range (Fig. 5A). Focal macular cone ERGs,20,21 which represent responses of the 15°,10°,or5° of the macula, were recorded from proband (IV-7), showing that the a- and b-waves as well as OPs were very reduced (Fig. 5B). Full-field ERGs and focal macular ERGs of the other family members were not performed.

DISCUSSION The GUCY2D gene is the third gene identiﬁed as causing autosomal dominant CORD.3 Mutations in this gene also cause

FIGURE 3. Fundus photographs (A, C, E, G, H) and ﬂuorescein fundus angiography (B, D, F) of patients with mutations of GUCY2D gene. (A, B) Left eye, case II-4; (C, D) left eye, case III-10; (E, F) left eye, case IV-7; (G) left eye, case III-2; (H) left eye, case IV-2.

The best-corrected visual acuity of the proband’s affected father (III -10) was 0.09 in the each eye at the age of 57 years. He apparently had macular degeneration in both eyes (Figs. 3C, 3D), with bilateral paracentral scotoma (Fig. 4B). He failed all of the Ishihara color plates, and also failed the panel D-15 test without any axis. The proband’s 83-year-old grandmother (II -4) had a more severe phenotype. Her best-corrected visual acuity was 0.05 in the right eye and 0.01 in the left. The central atrophic retinal lesions and the central scotoma were larger than that of her son (Figs. 3A, 3B, 4A). She was barely able to perform the Ishihara color vision and panel D-15 tests because of her poor vision. Another young affected member in another branch of this family (IV-2; 29-years-old, with corrected visual acuity of 0.2 in each eye) had only mild fundus changes (Fig. 3H) with almost normal visual ﬁeld, that were similar to those of the proband (IV-7). She failed the panel D-15 test without any axis. Her 62-year-old affected father (III-2) showed macular dystrophy (Fig. 3G) and paracentral scotoma above the center in each eye (Fig. 4D), that were similar to those in the proband’s affected father (III -10). All four unaffected family members had good best-corrected visual acuities of Ͼ 1.2 in both eyes with normal visual ﬁelds, FIGURE 4. Goldmann kinetic perimetry using indicated isopters. (A) normal color visions, and normal fundus appearances. The Case II-4; (B) case III-10; (C) case IV-7; (D) case III-2.

Downloaded from jov.arvojournals.org on 10/01/2021 1484 Ito et al. IOVS, May 2004, Vol. 45, No. 5

FIGURE 5. (A) Full-ﬁeld ERGs recorded after 30 minutes of dark-adap- tation in a normal subject and case IV-7. The arrowheads indicate the stimulus onsets. (B) Focal macular cone ERGs recorded in a normal subject and case IV-7.

Leber congenital amaurosis (LCA), a more severe, early onset descriptions of the phenotypes associated with codon 838 autosomal recessive retinal dystrophy.12,22 However, the mu- mutations,3,13,15,17,29 indicating that patients with CORD tations for LCA are causative in the homozygous or compound caused by the GUCY2D mutations have an overall clinical heterozygous state, and heterozygous carriers of the mutations phenotype similar to that with codon 838 even when the show essentially normal clinical phenotype except for subclin- mutation is not associated with a codon 838 substitution. ical mild reduction of cone and rod ERGs.23 Only mutations Until now, only one large mutation screening of this gene associated with codon 8383,14–17 have been reported to cause has been conducted.14 A group of 40 patients, 27 with auto- the apparent ocular phenotype, CORD, in the heterozygous somal dominant MD and 13 with autosomal dominant CORD or state. COD, was screened, and three probands (7.5%) were identified These results would indicate that codon 838 is an important as having mutations in the gene.14 In the present study, the amino acid in RetGC-1, and in fact, an in vitro study has shown frequency was almost the same; 3 out of 38 probands (7.8%) that the R838C mutation increases the affinity of recombinant with CORD had GUCY2D mutations. However, the frequency ϩ RetGC-1 for GCAP1 and alters the Ca2 sensitivity of GCAP1 became higher at 30% if we limited the subjects only to appar- response. The mutant can be stimulated by GCAP1 at higher ent autosomal dominant families, because only 10 out of the 38 ϩ Ca2 concentrations than the wild type, which then causes a families had apparent autosomal dominant inheritance pattern. higher than normal rate of cGMP synthesis in dark-adapted These results suggested that GUCY2D mutations are relatively photoreceptors, resulting in cone and rod degeneration.24 common as the cause of autosomal dominant CORD in the The report of novel I915TϩG917R mutations in an autoso- Japanese population. mal dominant CORD family is the first to show that a heterozy- Whether the codon 838 mutations arose separately or from gous mutation of GUCY2D not involving codon 838 is caus- a common ancestor was not determined, because all previously ative for CORD. Although an in vitro study was not performed, reported GUCY2D mutations were found in white popula- the codons 915 and/or 917 were assumed to be important for tions. A haplotype analysis conducted among five families with the function of RetGC-1, because amino acid substitutions of R838C substitution could not answer this question.14 Our these codons caused apparent ocular phenotypes in a het- results that R838H and R838C mutations were present in Jap- erozygous state similar to those of codon 838. In addition, anese patients far from Europe would suggest that codon 838 alignment of part of this domain from human RetGC-1 and four is a determinant for dominant CORD. 25 other members of the subgroup (human RetGC-2, rat GC-E, In conclusion, novel complex mutations of I915TϩG917R 26 27 GC-F, and bovine ROS-GC ) show that both Ile915 and in the GUCY2D gene were analyzed and the phenotypes de- Gly917 are fully conserved among sensory cyclase family mem- scribed in an autosomal dominant CORD family. This is the first bers (Fig. 2D). With the I915TϩG917R mutations, the charac- report showing that a GUCY2D mutation not involving codon teristics of the amino acid change from hydrophobic to hydro- 838 can cause autosomal dominant CORD. philic in codon 915, and from neutral to basic in codon 917. The codons 915 and 917 are located within the putative catalytic domain of the RetGC-1 protein,18 and the secondary References structure of the RetGC-1 protein predicted using the 3D-1D 28 1. Freund CL, Gregory-Evans CY, et al. Cone-rod dystrophy due to compatibility algorithm from the SSThread Program (http:// mutations in a novel photoreceptor-specific homeobox gene www.ddbj.nig.ac.jp/E-mail/ssthread/welcome.html) was sig- (CRX) essential for maintenance of the photoreceptor. Cell. 1997; nificantly changed in both the dimerization and catalytic do- 91:543–553. mains by both or either amino acid changes (data not shown). 2. Swain PK, Chen S, Wang QL, et al. Mutations in the cone-rod Whether only one of the mutations caused the clinical pheno- homeobox gene are associated with the cone-rod dystrophy pho- type or both are concerned with the disease cooperatively was toreceptor degeneration. Neuron. 1997;19:1329–1336. not determined. Possibly one of the mutations is critical and 3. Kelsell RE, Gregory-Evans K, Payne AM, et al. Mutations in the another is a secondary mutation. retinal guanylate cyclase (RETGC-1) gene in dominant cone-rod In the clinical phenotype of the affected members of the dystrophy. Hum Mol Genet. 1998;7:1179–1184. family with the I915TϩG917R mutations, the visual acuity of 4. Sohocki MM, Perrault I, Leroy BP, et al. Prevalence of AIPL1 the young 20Јs patients (IV-7 and IV-2) was between 0.1 and mutations in inherited retinal degenerative disease. Mol Genet 0.2 with almost normal fundus and normal visual fields. The Metab. 2000;70:142–150. ERGs in the young proband (IV-7) demonstrated severely re- 5. Payne AM, Downes SM, Bessant DA, et al. A mutation in guanylate duced cone function and nearly normal rod function (Fig. 5A). cyclase activator 1A (GUCA1A) in an autosomal dominant cone dystrophy pedigree mapping to a new locus on chromosome The visual acuity in patients at approximately 60 years of age Ͻ 6p21.1. Hum Mol Genet. 1998;7:273–277. (III-2 and III-10) was 0.1 when macular degeneration became 6. Johnson S, Halford S, Morris AG, et al. Genomic organization and apparent with the presence of central scotoma. Color vision alternative splicing of human RIM1, a gene implicated in autoso- was impaired without any axis. The peripheral visual fields mal dominant cone-rod dystrophy (CORD7). Genomics. 2003;81: were relatively well-preserved even in the elderly patients (Fig. 304–314. 4), and the central scotomas were more likely to be the upper 7. Kobayashi A, Higashide T, Hamasaki D, et al. HRG4 (UNC119) area of the macula. These findings were similar to the previous mutation found in cone-rod dystrophy causes retinal degeneration

Downloaded from jov.arvojournals.org on 10/01/2021 IOVS, May 2004, Vol. 45, No. 5 Novel Double GUCY2D Mutation in CORD Family 1485

in a transgenic model. Invest Ophthalmol Vis Sci. 2000;41:3268– 18. Kelsell RE, Godley BF, Evans K, et al. Localization of the gene for 3277. progressive bifocal chorioretinal atrophy (PBCRA) to chromosome 8. Cremers FP, van de Pol DJ, van Driel M, et al. Autosomal recessive 6q. Hum Mol Genet. 1995;4:1653–1656. retinitis pigmentosa and cone-rod dystrophy caused by splice site 19. Nakamura M, Ito S, Terasaki H, Miyake Y. Novel CACNA1F muta- mutations in the Stargardt’s disease gene ABCR. Hum Mol Genet. tions in Japanese patients with incomplete congenital stationary 1998;7:355–362. night blindness. Invest Ophthalmol Vis Sci. 2001 Jun;42:1610– 9. Nakamura M, Hotta Y, Tanikawa A, Terasaki H, Miyake Y. A high 1616. association with cone dystrophy in fundus albipunctatus caused by 20. Miyake Y, Shiroyama I, Ota I, Horiguchi M. Oscillatory potentials in Invest Ophthal- mutations of the RDH5 gene. Invest Ophthalmol Vis Sci. 2000;41: electroretinograms of the human macular region. mol Vis Sci. 1988;29:1631–1635. 3925–3932. 21. Miyake Y, Shiroyama I, Ota I, Horiguchi M. Focal macular electro- 10. Demirci FY, Rigatti BW, Wen G, et al. X-linked cone-rod dystrophy retinogram in X-linked congenital retinoschisis. Invest Ophthal- (locus COD1): identification of mutations in RPGR exon ORF15. mol Vis Sci. 1993;34:512–515. Am J Hum Genet . 2002;70:1049–1053. 22. Perrault I, Rozet JM, Gerber S, et al. Spectrum of retGC1 mutations 11. Laura RP, Dizhoor AM, Hurley JB. The membrane guanylyl cyclase, in Leber’s congenital amaurosis. Eur J Hum Genet. 2000;8:578– retinal guanylyl cyclase-1, is activated through its intracellular 582. domain. J Biol Chem. 1996;271:11646–11651. 23. Koenekoop RK, Fishman GA, Iannaccone A, et al. Electroretino- 12. Perrault I, Rozet JM, Calvas P, et al. Retinal-specific guanylate graphic abnormalities in parents of patients with Leber congenital cyclase gene mutations in Leber’s congenital amaurosis. Nature amaurosis who have heterozygous GUCY2D mutations. Arch Oph- genetics. 1996;14:461–464. thalmol. 2002;120:1325–1330. 13. Gregory-Evans K, Kelsell RE, Gregory-Evans CY, et al. Autosomal 24. Tucker CL, Woodcock SC, Kelsell RE, Ramamurthy V, Hunt DM, dominant cone-rod retinal dystrophy (CORD6) from heterozygous Hurley JB. Biochemical analysis of a dimerization domain mutation mutation of GUCY2D, which encodes retinal guanylate cyclase. in RetGC-1 associated with dominant cone-rod dystrophy. Proc Ophthalmology. 2000;107:55–61. Natl Acad Sci USA. 1999;96:9039–9044. 14. Payne AM, Morris AG, Downes SM, et al. Clustering and frequency 25. Lowe DG, Dizhoor AM, Liu K, et al. Cloning and expression of of mutations in the retinal guanylate cyclase (GUCY2D) gene in a second photoreceptor-specific membrane retina guanylyl cy- patients with dominant cone-rod dystrophies. J Med Genet. 2001; clase (RetGC), RetGC-2. Proc Natl Acad Sci USA. 1995;92:5535– 38:611–614. 5539. 26. Yang RB, Foster DC, Garbers DL, Fulle HJ. Two membrane forms 15. Van Ghelue M, Eriksen HL, Ponjavic V, et al. Autosomal dominant of guanylyl cyclase found in the eye. Proc Natl Acad Sci USA. cone-rod dystrophy due to a missense mutation (R838C) in the 1995;92:602–606. guanylate cyclase 2D gene (GUCY2D) with preserved rod function 27. Goraczniak RM, Duda T, Sitaramayya A, Sharma RK. Structural and Ophthalmic Genetics in one branch of the family. . 2000;21:197–209. functional characterization of the rod outer segment membrane 16. Weigell-Weber M, Fokstuen S, Torok B, Niemeyer G, Schinzel A, guanylate cyclase. Biochem J. 1994;302:455–461. Hergersberg M. Codons 837 and 838 in the retinal guanylate 28. Ito M, Matsuo Y, Nishikawa K. Prediction of protein secondary cyclase gene on chromosome 17p: hot spots for mutations in structure using the 3D–1D compatibility algorithm. Comput Appl autosomal dominant cone-rod dystrophy? Arch Ophthalmol. 2000; Biosci. 1997;13:415–424. 118:300. 29. Downes SM, Payne AM, Kelsell RE, et al. Autosomal dominant 17. Perrault I, Rozet JM, Gerber S, et al. A retGC-1 Mutation in auto- cone-rod dystrophy with mutations in the guanylate cyclase 2D somal dominant cone-rod dystrophy. Am J Hum Genet. 1998;63: gene encoding retinal guanylate cyclase-1. Arch Ophthalmol. 651–654. 2001;119:1667–1673.

Downloaded from jov.arvojournals.org on 10/01/2021