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From the Department of Ophthalmology, Nagoya University School of Medicine, Nagoya, Japan.
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Abstract |
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METHODS. Fourteen patients from 12 separate Japanese families with fundus albipunctatus were examined. Six of the patients from 6 families also had a cone dystrophy. Genomic DNA was extracted from leukocytes of the peripheral blood, and exons 2, 3, 4, and 5 of the RDH5 gene were amplified by polymerase chain reaction and were directly sequenced. A complete ophthalmic examination was performed including best-corrected visual acuity, slit-lamp examination, indirect ophthalmoscopy, fundus photography, and electroretinography.
RESULTS. In all the patients, either a homozygous mutation or compound heterozygous mutations in the RDH5 gene were identified. The identified mutations were nucleotide position (nt) 103 G to A (Gly35Ser), nt 319 G to C (Gly107Arg), nt 394 G to A (Val132Met), nt 719 G insertion (frame shift), nt 839 G to A (Arg280His), nt 841 T to C (Tyr281His), and nt 928 C to GAAG (Leu310 to GluVal). All these mutations except the Arg280His were new. The nt 928 C to GAAG mutation was detected in patients with and without cone dystrophy. Cone dystrophy was most frequently seen in patients over 40 years old.
CONCLUSIONS. Fundus albipunctatus either with or without cone dystrophy is caused by mutations of the RDH5 gene. Cone dystrophy is frequently observed in elderly patients with fundus albipunctatus. The conclusion was reached that the mutations of the RDH5 gene caused a progressive cone dystrophy as well as night blindness.
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Introduction |
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Similar yellow-white lesions are observed in patients with retinitis punctata albescense, a kind of retinitis pigmentosa (RP).5 In such cases, there is a progressive decline of visual functions with decreasing visual acuity and the development of visual field defects. Both scotopic and photopic ERG responses are reduced and do not recover even after a long period of dark adaptation. The final clinical feature of this disease is the appearance of typical RP lesions, with disappearance of the white punctata. A mutation was found in the human peripherin/RDS gene in a family of this disease,6 and recent study revealed recessive mutations in the RLBP1 gene encoding cellular retinaldehyde-binding protein (CRALBP) causes a type of this disease.7 8
It was recently reported that mutations of the 11-cis retinol dehydrogenase (RDH5) gene, which is expressed predominantly in RPE, cause fundus albipunctatus.9 These authors reported that a homozygous missense mutation, Gly238Trp (GGG to TGG), and compound heterozygous missense mutations, Gly238Trp (GGG to TGG) and Ser73Phe (TCC to TTC) of the RDH5 gene, were detected in a 49-year-old patient and a 16-year-old patient, respectively. However, no mutation in this gene was found in 29 cases of retinitis punctata albescens, 71 cases of autosomal recessive RP, 73 cases of autosomal dominant RP, and 94 normal controls.7 Gonzalez-Fernandez et al.10 examined the RDH5 gene of 2 patients with fundus albipunctatus and found a homozygous missense mutation, Gly238Trp (GGG to TGG) in a 26-year-old patient and compound heterozygous missense mutations, Arg280His (CGC to CAC) and Ala294Pro (GCC to CCC) in a 28-year-old patient.
Approximately 10 years ago, we reported five cases of fundus albipunctatus associated with cone dystrophy whose full-field photopic ERGs were severely reduced.11 At that time, we stated that we could not determine with the available data whether these cases represented an advanced stage of fundus albipunctatus or a distinct disease entity. We also could not state whether these cases represented a chance combination of fundus albipunctatus and cone dystrophy in the same patient.11 After that, we reported that between 1979 and 1993, 27 patients with fundus albipunctatus visited our clinic; 7 (26%) of them were affected by Bull’s eye or similar lesions.12 The subjects without macular lesions ranged in age from 5 to 51 years (mean, 18 years), whereas the 7 with macular lesion ranged in age from 36 to 54 years (mean, 44 years), and we suggested the possible occurrence of macular lesions during the natural course of fundus albipunctatus.12 However, we could not confirm genetically at that time. To settle this uncertainty, we have reexamined 3 of these patients as well as 3 additional male patients from 6 separate Japanese families with fundus albipunctatus and cone dystrophy as well as 8 patients from 6 separate Japanese families with fundus albipunctatus in whom cone dystrophy was not seen. We shall show that a homozygous mutation or compound heterozygous mutations in the RDH5 gene were detected in all the patients. Because there was a progressive decline of the visual functions in some aged patients, we conclude that these mutations of the RDH5 gene lead to a progressive cone dystrophy as well as the congenital night blindness.
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Methods |
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Informed consent was obtained from the subjects after an explanation of this study. Genomic DNA was extracted from leukocytes of peripheral blood from each patient. Exons 2, 3, 4, and 5 of the RDH5 gene were amplified by polymerase chain reaction (PCR) using the DNA Thermal Cycler 9700 (Perkin Elmer Applied Biosystems, Foster City, CA). Primers were purchased from Life Technologies Oriental, Inc. (Tokyo, Japan) following the sequences published previously by Yamamoto et al.9 Genomic DNA (200 ng) was PCR amplified in 50 µl reactions containing Amplitaq Gold Taq DNA polymerase (Perkin Elmer Applied Biosystems). The PCR conditions were as follows: 5 minutes at 94°C, 35 cycles at 94°C for 30 seconds, followed by 30 seconds at 50o to 60°C (exon 2a, 3b, 5a, 50°C; exon 3a, 4, 5b, 54°C; exon 2b, 2c, 60°C), and 45 seconds at 72°C with a final extension step at 72°C for 7 minutes. The PCR products were purified using High Pure PCR Purification Kit (Boehringer Mannheim GmbH, Mannheim, Germany) and then directly sequenced using a DNA sequencing kit (Dye Terminator Cycle Sequencing Ready Reaction Kit; Perkin Elmer Applied Biosystems, Foster City, CA), and an automated DNA sequencer (Model 373; Applied Biosystems, Foster City, CA). Primers for the sequence reaction were the same as those for the PCR reaction. All samples were sequenced on both sense and antisense strands. To search for polymorphisms, the exons of the RDH5 gene from 90 alleles (24 men and 21 women) from unrelated normal Japanese individuals were directly sequenced. In addition, all exons of RDH5 gene from 10 patients with cone dystrophy who did not have fundus albipunctatus were also examined.
Conventional ERGs were elicited with Ganzfeld stimuli after 30 minutes of dark adaptation. The rod (scotopic) ERGs were recorded with a blue light at an intensity of 5.2 x 10-3 cd/m2 per sec. The mixed rod:cone single flash ERGs were recorded with a white stimulus at an intensity of 44.2 cd/m2 per sec. The cone ERG and the 30-Hz flicker ERG were elicited with a white stimulus at an intensity of 4 and 0.9 cd/m2 per sec, respectively.
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Results |
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Case Reports |
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Case 1 is a 63-year-old man who was described in detail 10 years
earlier (1992; case 1 in Ref. 11)
. In 1999, the bull’s eye maculopathy
had enlarged in both fundus (Fig. 2A
, compare with Fig. 1A
of Ref. 11)
, and the visual acuity of the right
eye was reduced from 0.6 to 0.1. The central scotomas were enlarged in
both eyes as determined by Goldmann perimetry.
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Case 3 is a 58-year-old man who was also described previously (1992; case 3 in Ref. 11 ). In 1981, when the patient was 40 years old, the fundus demonstrated a typical fundus albipunctatus, and his visual acuity was 1.2 in both eyes. Eight years later, in 1989, we recognized the macular changes as an early stage of bull’s eye maculopathy. Localized chorioretinal atrophy was recognized in the both eyes. In 1999, the bull’s eye maculopathy was more prominent in both eyes (Fig. 2D , compare with Fig. 4 of Ref. 11 ). However, the visual acuity of both eyes remained at 1.2.
Case 4 is a 48-year-old man with night blindness who noticed a progressive decrease in his vision and a reduction in the size of his visual field over the previous 10 years. His corrected visual acuity was 0.03 in each eye. There was no abnormality in the anterior segment and the media. Numerous yellow-white dots were observed in the fundi, and the both maculas demonstrated a bull’s eye lesion (Fig. 2E) . His parents were not consanguineous, and his pedigree contained no other member with night blindness or low visual acuity. A central scotoma was detected in both eyes by Goldmann perimetry.
Full-field ERGs after 30 minutes of dark adaptation showed no rod response, a reduced cone b-wave with delayed implicit times, and a moderately reduced 30-Hz flicker response. Single bright-flash ERGs showed a severely reduced b-wave and moderately decreased a-wave. After 3 hours of dark adaptation, a rod b-wave was recorded (amplitude, 236 µV), with a normal implicit time. Single bright-flash ERG showed an increase in the amplitude of the a- and b-waves (Fig. 3) .
Case 5 is a 65-year-old man with night blindness who reported a progressive decrease in his vision. In 1989 his corrected visual acuity was 0.6 OD and 0.7 OS. His pedigree contained no other members with night blindness or low visual acuity, and no consanguinity was reported in his family.
His fundus demonstrated multiple yellow-white dots mainly in the midperiphery and degenerative changes in the periphery (Fig. 2G) . The macula of the right eye showed a bull’s eye maculopathy (Fig. 2F) , but only atrophic changes were observed in the left macula. There was no vessel attenuation. Color vision tests revealed a severe blue-yellow defect.
Full-field ERG recordings demonstrated that rod, cone, and 30-Hz flicker responses were not present after 30 minutes of dark adaptation. Single bright-flash ERGs showed severely reduced a- and b-waves. After 2 hours of dark adaptation, only a very small rod b-wave of 19 µV was recorded, and single bright-flash ERGs showed a slightly larger a- and b-waves.
In 1999, when he was 65-year-old, his corrected visual acuity was reduced to 0.07 OD and 0.2 OS. The bull’s eye in the right eye had enlarged, and a definite bull’s eye was observed in the left eye. It was difficult to recognize the white punctate lesions in the fundus.
Case 6 is a 74-year-old man with night blindness who had noticed a gradual reduction of vision and a central scotoma over the previous 2 years. In 1995, his corrected visual acuity was 0.3 in both eyes. His healthy parents were first cousins. His younger sister had severely reduced vision. Tiny white, dot-like lesions were seen over the fundi, and bull’s eye maculopathy was observed in both maculas (Fig. 2H) . Slight cataracts were seen in the both eyes. The peripheral visual fields were normal but the central sensitivity was decreased in both eyes.
Full-field ERGs recorded from the left eye after 30 minutes of dark adaptation showed that both rod and cone b-waves were significantly reduced. The 30-Hz flicker responses were also reduced. A single bright-flash ERG showed moderately decreased a- and b-waves. After 3 hours of dark-adaptation the rod b-wave improved to an amplitude of 73 µV, whereas the single, bright-flash ERG recorded approximately the same amplitude a- and b-waves (Fig. 3) . He underwent cataract operations in the both eyes in 1996. In 1999 his visual acuity was reduced to 0.02 OD and 0.06 OS.
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Discussion |
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In this study, mutations of the RDH5 gene were detected in all patients with fundus albipunctatus either with or without cone dystrophy. The cone dystrophy with significantly reduced photopic ERG responses was found in all but one elderly patient with fundus albipunctatus, and even in the elderly patient without cone dystrophy, her photopic ERGs were reduced. This suggests that the association of fundus albipunctatus with cone dystrophy was not due to a chance association of a mutation in two genes.
A major mutation of RDH5 gene, nt 928 C to GAAG, was identified in patients either with or without cone dystrophy. These results led us to suppose that the cone dysfunction was frequently observed in elderly patients with fundus albipunctatus, in whom cone dystrophy with bull’s eye accompanied the fundus albipunctatus, resulting in severe loss of visual function. Because the nt 928 C to GAAG mutation in the RDH5 gene was found in 10 cases out of 13, this mutation may occur at a relatively high frequency in Japanese patients with fundus albipunctatus. Also, because this kind of base change mutation is rare, we suggest that our patients with this mutation probably originated from a common ancestor who lived many years ago in Japan. In the fundus albipunctatus patients over 40 years of age with the homozygous or heterozygous mutation, a cone dystrophy with bull’s eye maculopathy and significantly reduced photopic b responses were found to accompany the fundus albipunctatus. In contrast, patients less than 20 years old with this mutation did not have cone dystrophy. Because it is possible that they will show the cone dystrophy in the future, it is important to follow these cases for a long time. There were phenotypic differences between cases 1 to 5 with the same homozygous nt 928 mutation and cone dystrophy. For example, visual acuity of case 4 began to be reduced in his thirties and was 0.03 when he was 41 years old. Case 3 started to show macular abnormality after 50 years of age, and his visual acuity was maintained at 1.2 when he was 58 years old. The local chorioretinal atrophies outside the maculas appeared in cases 2, 3, and 5 but not in cases 1 and 4. These phenotypic differences including the clinical course and extent of the disease may be due to acquired factors such as the living environment and customs. In addition, other genetic factors may also play a role. In any case, our results have demonstrated that both the homozygous and heterozygous 928 C to GAAG mutation leads to the cone dystrophy with its manifestation at an older age.
The brothers, cases 12 and 13 with the homozygous Gly35Ser mutation, showed typical fundus albipunctatus without cone dystrophy. However, their cones were probably altered because the photopic ERGs were significantly reduced. One patient (case 11) with compound heterozygous mutations of nt 928 C to GAAG and Gly35Ser showed significantly reduced photopic ERG response, in spite of being only 20 years old. This suggests that the cone function of some patients with fundus albipunctatus can be altered from a young age. It is not known whether all the young patients with fundus albipunctatus will develop cone dystrophy. It is important to follow these patients, and more data are needed to determine the relationship between genotype and phenotype of fundus albipunctatus and its association with cone dystrophy.
We have noted that the size and the number of the white punctata decreased with age, and the white dots become inconspicuous in older patients. For example, in patients with homozygous nt 928 C to GAAG mutation, numerous distinct white dots were observed in the younger patients (cases 7–9; Figs. 2I 2J ), but they were not conspicuous in the older patients (cases 1–4; Figs. 2A 2B 2C 2D ). The white punctata were clearly observed in all the young patients, including those with other mutations (case 7–13; Figs. 2I 2J 2K ), but it was more inconspicuous in an older patient, even without cone dystrophy (case 14; Fig. 2L ). It may be possible that the white lesions will become inconspicuous or disappear at the end stage of fundus albipunctatus when only retinal degeneration is clearly observed. In such an end stage, both scotopic and photopic ERGs may be severely reduced and do not recover even after a long dark-adaptation time, as in case 5. In such cases, it will be difficult to diagnose the difference between fundus albipunctatus and retinitis punctata albescence, and probably only genetic examination can make the diagnosis.
Recently, additional genes causing cone dystrophies have been identified. Mutations of the cone-rod homeobox (CRX) gene, which is important for photoreceptor development, causes autosomal dominant cone-rod dystrophy.16 17 In Crx-/- mice, the outer segments of photoreceptor do not develop.18 In adult mice, CRX is specifically expressed in photoreceptor cells and pinealocytes of pineal gland and activate the expressions of photoreceptor-specific genes, including rhodopsin, arrestin, and IRBP. Mutations of retinal guanylate cyclase (RetGC-1), which is a retina-specific, Ca2+-regulated membrane guanylate cyclase and is pivotal for vertebrae phototransduction, also causes autosomal dominant cone-rod dystrophy.19 A specific mutation (Y99C) has been found in the gene for guanylate cyclase activator 1A (GUCA1A) that encodes a guanylate cyclase–activating protein (GCAP1), which is a calcium-binding protein expressed predominantly in the outer segments of photoreceptors. GCAP1 plays an important role in the recovery phase of phototransduction by activating RetGC-1, and mutation of this protein leads to autosomal dominant cone dystrophy.20 21 22 In addition, Val20Glu, Asn244His and Tyr184Ser mutations of the peripherin/RDS gene were found in some patients with autosomal dominant cone-rod dystrophy.23 24 Mutation in the splice site of retina-specific ATP-binding cassette transporter (ABCR) gene, which causes Stargardt disease, was found in a family of autosomal recessive cone dystrophy.25
Our cases are the first showing that mutations of the RDH5 gene causes cone dystrophy, and to our best of knowledge, this is the sixth gene that causes cone dystrophy. This is also the first report of a gene expressed in the RPE causing cone dystrophy, because all other known genes causing cone dystrophy are expressed in photoreceptor cells. Although the exact mechanism whereby mutations lead to cone dystrophy is unknown, the RDH5 gene appears important for maintenance of normal cone function.
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Acknowledgements |
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Footnotes |
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Submitted for publication April 17, 2000; revised June 26, 2000; accepted July 19, 2000.
Commercial relationships policy: N.
Corresponding author: Makoto Nakamura, Department of Ophthalmology, Nagoya University School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8560, Japan. makonaka{at}med.nagoya-u.ac.jp
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