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Novel 615delC mutation in the CRX gene in a Japanese family with cone-rod dystrophy
3. Darlet RW, Heischober B. Methamphetamine: stimulant of the 1990’s? West J Med 1990;153:625– 628. 4. Morbidity and Mortality Report. Center for Disease Control. U.S. Department of Public Health. 2000;49(45):1021–1024. 5. Hughes WF. Alkali burns of the cornea. I. Review of the literature and summary of present knowledge. Arch Ophthalmol 1946;35:423– 426.
Novel 615delC Mutation in the CRX Gene in a Japanese Family With Cone-Rod Dystrophy Toshitaka Itabashi, MD, Yuko Wada, MD, Hajime Sato, MD, Miyuki Kawamura, MD, Takashi Shiono, MD, and Makoto Tamai, MD PURPOSE: To characterize the clinical features of a Japanese family with cone-rod dystrophy associated with a novel 615delC mutation in the cone-rod homeobox (CRX) gene. DESIGN: Case reports and results of DNA analysis. METHODS: Mutational screening by direct sequencing was performed for the three exons in the CRX gene. The clinical features were evaluated by visual acuity measurements, electroretinography, and kinetic visual field testing. RESULTS: A 615delC mutation in the CRX gene was identified and found to cosegregate with cone-rod dystrophy. The ophthalmic findings included cone-rod dystrophy with negative-type electroretinograms (ERGs) and a rapid progression after the age of 40 years. CONCLUSION: These findings indicate that the 615delC mutation causes cone-rod dystrophy with a negative-type ERG. The genotype–phenotype correlation in the CRX gene in our patient and others reported in the literature suggest that the negative-type ERG might be a good sign for having a mutation in the CRX gene. (Am J Ophthalmol 2004;138:876 – 877. © 2004 by Elsevier Inc. All rights reserved.)
T
FIGURE 1. (A) Pedigree of a Japanese family with cone-rod dystrophy. Solid symbols are the affected members and open symbols are unaffected members. Arrow ⴝ proband; squares ⴝ male members; circles ⴝ female members; M ⴝ mutant allele; plus ⴝ normal allele. (B) Results of nucleotide sequencing analysis. Sequence analysis of exon 1 in patient II-2 showing the heterozygous 615delC mutation. Arrows indicate the position of the mutation.
paid to the natural course of the ophthalmologic characteristics of the proband and the molecular genetic analysis. After obtaining written informed consent, two members of a family underwent molecular genetic analysis (Figure 1A). The sequences from exon 1 to exon 3 of the CRX gene were amplified by polymerase chain reaction (PCR). The products of PCR were directly sequenced by an ABI sequencer (Model 3100, Applied Biosystems, Foster City, California). The molecular genetic analysis demonstrated that the proband had a novel 615delC mutation in the CRX gene, and a nonaffected member did not have this mutation. This mutation resulted in a premature termination at codon 218 (Figure 1B). The natural course of the ophthalmologic characteristics can be determined by examining patient II-2 who was followed from age 45 years to 56 years. This patient reported a progressive decreased visual acuity and increase of metamorphopsia beginning at age 45. His visual acuity
HE CONE-ROD HOMEOBOX GENE (CRX) PLAYS A ROLE IN
the regulation of the expression of specific photoreceptor genes and also in the maintenance of normal rod and cone function.1 It has been established that mutations in the CRX gene cause autosomal dominant cone-rod dystrophy and Leber’s congenital amaurosis.1–3 We report the ocular findings associated with a novel 615delC mutation in the CRX gene. Special attention was Accepted for publication May 25, 2004. From the Department of Ophthalmology, Tohoku University School of Medicine, Sendai, Japan (T.I., Y.W., H.S., M.K., M.T.), and Shiono Ganka Clinic, Japan (T.S.). Inquiries to Toshitaka Itabashi, MD, Department of Ophthalmology, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan; fax: ⫹81-22-717-7298; e-mail: [email protected]
876
AMERICAN JOURNAL
OF
OPHTHALMOLOGY
NOVEMBER 2004
FIGURE 2. (A) Fundus photographs of Patient II-2 at age 45 years showing hypopigmented atrophic lesion around macula without attenuation of retinal vessels. (B) Same patient as in A at age 56 years. The progression of retinal degeneration and atrophic macular degeneration can be seen. (C) and (D) Results of Goldmann’s visual field testing at age 45 years (C) and at age 56 years (D). The enlargement of central scotoma can be seen in the intervening 11 years. (E) and (F) Results of electroretinography (ERG) at age 45 years (E) and at age 56 years (F) showing negative ERGs. No remarkable change can be seen in the intervening 11 years.
at age 45 was corrected to 0.8 OD with ⫺3.5 to 1.5 ⫻ 30 degrees diopters (D) and 0.6 OS with ⫺1.5 D. Fundus examination showed hypopigmented atrophic lesions around the macula bilaterally (Figure 2A). Kinetic visual field testing detected a central scotoma with well-preserved peripheral field (Figure 2C). The mixed cone-rod flash electroretinogram (ERG) showed a negative-type ERG bilaterally (Figure 2E).4 The patient’s visual acuity decreased after his first visit in 1992, and at age 56 in 2004, his visual acuity was corrected to 0.02 OD with a ⫺3.0 to 1.0 ⫻ 60 degrees D and to 0.01 OS with a ⫺3.0 to 1.0 ⫻ 120 degrees D. Fundus examination showed an increase of pigmentation, atrophy of the retinal pigment epithelium, and atrophic macular degeneration. Bone spicule pigmentation was seen in the nasal area (Figure 2B). Kinetic visual field testing showed an enlargement of the central and paracentral scotomas bilaterally (Figure 2D). Electroretinogram testing showed no remarkable change during the intervening 6 years (Figure 2F). Our patient noted visual disturbances after age 40 and showed severe clinical features after age 50. These findings suggest that Japanese patients associated with the CRX mutations might have a rapid progressive decline of visual function after age 40. It has been reported that ERGs of patients with the Arg41Trp mutation showed a negative-type ERG to a VOL. 138, NO. 5
bright flash.1 Our patients with the 615delC mutation also showed the negative-type ERG (Figures 2E and 2F). Conversely, we have reported one Japanese family associated with the Arg41Trp mutation whose affected members did not have the negative-type ERG.5 Although these findings suggest that mutations in the CRX gene for CRD are variable, the negative-type ERG should be considered as a good sign for having a mutation of the CRX gene. REFERENCES
1. Swain PK, Chen S, Wang QL, et al. Mutations in the cone-rod homeobox gene are associated with the cone-rod dystrophy photoreceptor degeneration. Neuron 1997;19: 1329 –1336. 2. Freund CL, Gregory-Evans CY, Furukawa T, et al. Cone-rod dystrophy due to mutations in a novel photoreceptor-specific homeobox gene (CRX) essential for maintenance of the photoreceptor. Cell 1997;91:543–553. 3. Retina International Scientific Newsletter. Available at http://www.retina-international.org/sci-news/crxmut.htm Accessed February 10, 2004. 4. Fujii N, Shiono T, Wada Y, et al. Autosomal dominant cone-rod dystrophy with negative electroretinogram. Br J Ophthalmol 1995;79:916 –921. 5. Itabashi T, Wada Y, Sato H, et al. Ocular findings in a Japanese family with Arg41Trp mutation of the CRX gene. Graefes Arch Clin Exp Ophthalmol 2003;241:535–540.
BRIEF REPORTS
877
Novel 615delC Mutation in the CRX Gene in a Japanese Family With Cone-Rod Dystrophy Toshitaka Itabashi, MD, Yuko Wada, MD, Hajime Sato, MD, Miyuki Kawamura, MD, Takashi Shiono, MD, and Makoto Tamai, MD PURPOSE: To characterize the clinical features of a Japanese family with cone-rod dystrophy associated with a novel 615delC mutation in the cone-rod homeobox (CRX) gene. DESIGN: Case reports and results of DNA analysis. METHODS: Mutational screening by direct sequencing was performed for the three exons in the CRX gene. The clinical features were evaluated by visual acuity measurements, electroretinography, and kinetic visual field testing. RESULTS: A 615delC mutation in the CRX gene was identified and found to cosegregate with cone-rod dystrophy. The ophthalmic findings included cone-rod dystrophy with negative-type electroretinograms (ERGs) and a rapid progression after the age of 40 years. CONCLUSION: These findings indicate that the 615delC mutation causes cone-rod dystrophy with a negative-type ERG. The genotype–phenotype correlation in the CRX gene in our patient and others reported in the literature suggest that the negative-type ERG might be a good sign for having a mutation in the CRX gene. (Am J Ophthalmol 2004;138:876 – 877. © 2004 by Elsevier Inc. All rights reserved.)
T
FIGURE 1. (A) Pedigree of a Japanese family with cone-rod dystrophy. Solid symbols are the affected members and open symbols are unaffected members. Arrow ⴝ proband; squares ⴝ male members; circles ⴝ female members; M ⴝ mutant allele; plus ⴝ normal allele. (B) Results of nucleotide sequencing analysis. Sequence analysis of exon 1 in patient II-2 showing the heterozygous 615delC mutation. Arrows indicate the position of the mutation.
paid to the natural course of the ophthalmologic characteristics of the proband and the molecular genetic analysis. After obtaining written informed consent, two members of a family underwent molecular genetic analysis (Figure 1A). The sequences from exon 1 to exon 3 of the CRX gene were amplified by polymerase chain reaction (PCR). The products of PCR were directly sequenced by an ABI sequencer (Model 3100, Applied Biosystems, Foster City, California). The molecular genetic analysis demonstrated that the proband had a novel 615delC mutation in the CRX gene, and a nonaffected member did not have this mutation. This mutation resulted in a premature termination at codon 218 (Figure 1B). The natural course of the ophthalmologic characteristics can be determined by examining patient II-2 who was followed from age 45 years to 56 years. This patient reported a progressive decreased visual acuity and increase of metamorphopsia beginning at age 45. His visual acuity
HE CONE-ROD HOMEOBOX GENE (CRX) PLAYS A ROLE IN
the regulation of the expression of specific photoreceptor genes and also in the maintenance of normal rod and cone function.1 It has been established that mutations in the CRX gene cause autosomal dominant cone-rod dystrophy and Leber’s congenital amaurosis.1–3 We report the ocular findings associated with a novel 615delC mutation in the CRX gene. Special attention was Accepted for publication May 25, 2004. From the Department of Ophthalmology, Tohoku University School of Medicine, Sendai, Japan (T.I., Y.W., H.S., M.K., M.T.), and Shiono Ganka Clinic, Japan (T.S.). Inquiries to Toshitaka Itabashi, MD, Department of Ophthalmology, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan; fax: ⫹81-22-717-7298; e-mail: [email protected]
876
AMERICAN JOURNAL
OF
OPHTHALMOLOGY
NOVEMBER 2004
FIGURE 2. (A) Fundus photographs of Patient II-2 at age 45 years showing hypopigmented atrophic lesion around macula without attenuation of retinal vessels. (B) Same patient as in A at age 56 years. The progression of retinal degeneration and atrophic macular degeneration can be seen. (C) and (D) Results of Goldmann’s visual field testing at age 45 years (C) and at age 56 years (D). The enlargement of central scotoma can be seen in the intervening 11 years. (E) and (F) Results of electroretinography (ERG) at age 45 years (E) and at age 56 years (F) showing negative ERGs. No remarkable change can be seen in the intervening 11 years.
at age 45 was corrected to 0.8 OD with ⫺3.5 to 1.5 ⫻ 30 degrees diopters (D) and 0.6 OS with ⫺1.5 D. Fundus examination showed hypopigmented atrophic lesions around the macula bilaterally (Figure 2A). Kinetic visual field testing detected a central scotoma with well-preserved peripheral field (Figure 2C). The mixed cone-rod flash electroretinogram (ERG) showed a negative-type ERG bilaterally (Figure 2E).4 The patient’s visual acuity decreased after his first visit in 1992, and at age 56 in 2004, his visual acuity was corrected to 0.02 OD with a ⫺3.0 to 1.0 ⫻ 60 degrees D and to 0.01 OS with a ⫺3.0 to 1.0 ⫻ 120 degrees D. Fundus examination showed an increase of pigmentation, atrophy of the retinal pigment epithelium, and atrophic macular degeneration. Bone spicule pigmentation was seen in the nasal area (Figure 2B). Kinetic visual field testing showed an enlargement of the central and paracentral scotomas bilaterally (Figure 2D). Electroretinogram testing showed no remarkable change during the intervening 6 years (Figure 2F). Our patient noted visual disturbances after age 40 and showed severe clinical features after age 50. These findings suggest that Japanese patients associated with the CRX mutations might have a rapid progressive decline of visual function after age 40. It has been reported that ERGs of patients with the Arg41Trp mutation showed a negative-type ERG to a VOL. 138, NO. 5
bright flash.1 Our patients with the 615delC mutation also showed the negative-type ERG (Figures 2E and 2F). Conversely, we have reported one Japanese family associated with the Arg41Trp mutation whose affected members did not have the negative-type ERG.5 Although these findings suggest that mutations in the CRX gene for CRD are variable, the negative-type ERG should be considered as a good sign for having a mutation of the CRX gene. REFERENCES
1. Swain PK, Chen S, Wang QL, et al. Mutations in the cone-rod homeobox gene are associated with the cone-rod dystrophy photoreceptor degeneration. Neuron 1997;19: 1329 –1336. 2. Freund CL, Gregory-Evans CY, Furukawa T, et al. Cone-rod dystrophy due to mutations in a novel photoreceptor-specific homeobox gene (CRX) essential for maintenance of the photoreceptor. Cell 1997;91:543–553. 3. Retina International Scientific Newsletter. Available at http://www.retina-international.org/sci-news/crxmut.htm Accessed February 10, 2004. 4. Fujii N, Shiono T, Wada Y, et al. Autosomal dominant cone-rod dystrophy with negative electroretinogram. Br J Ophthalmol 1995;79:916 –921. 5. Itabashi T, Wada Y, Sato H, et al. Ocular findings in a Japanese family with Arg41Trp mutation of the CRX gene. Graefes Arch Clin Exp Ophthalmol 2003;241:535–540.
BRIEF REPORTS
877