OPHTHALMIC MOLECULAR GENETICS Gene Mutations in Autosomal Recessive Pigmentosa

Mitsuru Nakazawa, MD; Yuko Wada, MD; Makoto Tamai, MD

Objective: To assess the clinical and molecular ge- Results: We identified 3 unrelated patients with retini- netic studies of patients with autosomal recessive reti- tis pigmentosa associated with a homozygous 1-base- nitis pigmentosa associated with a mutation in the ar- pair deletion mutation in codon 309 of the arrestin gene restin gene. designated as 1147delA. All 3 patients showed pigmen- tary retinal degeneration in the midperipheral area with Design: Results of molecular genetic screening and case or without macular involvement. Patient 1 had a sibling reports with DNA analysis and clinical features. with Oguchi disease associated with the same mutation. Patient 2 demonstrated pigmentary retinal degenera- Setting: University medical center. tion associated with a golden-yellow reflex in the pe- ripheral . Patients 1 and 3 showed features of Patients: One hundred twenty anamnestically unre- without the golden-yellow fundus lated patients with autosomal recessive retinitis pig- reflex. mentosa. Conclusions: Although the arrestin 1147delA has been Methods: DNA analysis was performed by single strand known as a frequent cause of Oguchi disease, this mu- conformation polymorphism followed by nucleotide se- tation also may be related to the pathogenesis of auto- quencing to search for a mutation in exon 11 of the ar- somal recessive retinitis pigmentosa. This phenomenon restin gene. Clinical features were characterized by vi- may provide evidence of variable expressivity of the mu- sual acuity slitlamp biomicroscopy, fundus examinations, tation in the arrestin gene. fluorescein angiography, kinetic visual field testing, and . Arch Ophthalmol. 1998;116:498-501

ECENT MOLECULAR genetic nal degeneration is sometimes associated analyses of autosomal re- with Oguchi disease.4 These findings have cessive retinitis pigmen- suggested the possibility that mutations in tosa (RP) have revealed that the arrestin gene are related to not only mutations in the rhodop- Oguchi disease but also RP. We, there- Rsin, the ␣-or␤-subunit of rod cyclic- fore, screened 120 anamnestically unre- guanosine-monophosphate phospho- lated patients with autosomal recessive RP diesterase, and rod cyclic guanosine to search for mutations in exon 11 of the monophosphate–gated channel genes can arrestin gene by the method previously de- cause autosomal recessive RP in some scribed4 and detected the 1147delA mu- families.1 These mutations have been iden- tation in 3 patients. We describe in this re- tified in only a few families with autoso- port these 3 patients with autosomal mal recessive RP, however, and genetic recessive RP associated with a homozy- causes are still largely unknown in most gous 1147delA mutation in the arrestin patients. Oguchi disease is a form of con- gene. genital stationary night blindness inher- ited as an autosomal recessive trait, and REPORT OF CASES most Japanese patients with Oguchi dis- ease have had homozygous 1–base-pair de- CASE 1 From the Department of letion of the arrestin gene designated as 2 , Tohoku 1147delA mutation. Oguchi disease has A 58-year-old man had initially noticed University School of Medicine, also been reported in other members of night blindness during his early teens, Sendai, Japan. families with RP,3 and partial chorioreti- when he had been diagnosed by a local

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©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 ophthalmologist as having RP. After that, he had a ripheral and peripheral bilaterally (Figure 2, A). gradual progression of , including Fluorescein angiography revealed hypofluorescent constriction of his visual field and night blindness. His areas, indicating chorioretinal atrophy in the macular parents were first cousins. His 55-year-old sister and pericentral regions, and hyperfluorescent areas in (Figure 1, OG12) had Oguchi disease associated with the central and midperipheral regions bilaterally the arrestin 1147delA mutation.4 Fundus examination (Figure 3, A). A dark-adapted standard flash electro- showed atrophic macular lesions in both eyes associ- retinogram (ERG) disclosed decreased amplitudes of ated with pigmentary retinal degeneration in midpe- the a waves and extinguished amplitudes of the b waves. The amplitudes of the 30-Hz flicker ERG were reduced bilaterally. The scotopic ERG was not record- Family 1 Family 2 Family 3 able (Figure 4).

CASE 2

A 35-year-old man (Figure 1) had had impaired visual

1 OG12 23 acuity in his teens. In addition to a gradual progression of visual impairment, he noticed disturbance of his night vision. Fundus examination demonstrated bilateral pig- mentary retinal degeneration in the posterior portion that extended from the macular area to the midperipheral retina (Figure 2, B) and an abnormal golden-yellow fun- Figure 1. Pedigrees showing members with retinitis pigmentosa. Numbers 1, 2, and 3 indicate patients 1, 2, and 3, respectively. Squares indicate male dus reflex in the peripheral area (Figure 2, C) that showed members; circles, females; X, examined; slash, deceased; and a double line, the Mizuo-Nakamura phenomenon. Fluorescein angi- consanguineous marriage. The left halves of examined members indicate ography disclosed a diffuse hyperfluorescent area in the genotypes: closed symbols show homozygous 1147delA mutation; mixed open and closed symbols, heterozygous 1147delA mutation; and open posterior portion associated with hypofluorescent areas symbols, homozygous normal sequence. The right halves of examined in the pericentral region bilaterally (Figure 3, C). A dark- members indicate phenotypes: closed symbols show retinitis pigmentosa; a adapted standard ERG (Figure 4) showed severely re- hatched symbol (OG12), Oguchi disease; and open symbols, not affected. Not examined members shown by mixed open and closed symbols in the duced amplitudes of the a waves and extinguished re- right side indicate those anamnestically suspected of having retinitis sponses of the b waves. The amplitudes of the 30-Hz flicker pigmentosa. ERG were reduced bilaterally.

A B

C D Figure 2. A, The fundus of patient 1 at age 58 years. Pigmentary retinal degeneration in the midperipheral portion and atrophic are observed. B, The fundus of patient 2 at age 35 years. Pigmentary retinal degeneration in the posterior and midperipheral portions is associated with a golden-yellow fundus reflex in the periphery. C, The lower peripheral portion of the eye of patient 2. A golden-yellow fundus reflex is seen. D, The fundus of patient 3 at age 72 years. Pigmentary retinal degeneration is seen in the midperipheral portion, with the macular area appearing relatively normal.

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©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 Scotopic Blue Standard Flash 30-Hz Flicker on on on R R R Control L L L R Oguchi Disease R R (OG12) L L L

R R R Patient 1 L L L

R R R Patient 2 L L L

R R R Patient 3 A L L L 200 µV 200 µV 100 µV 20 ms 20 ms 10 ms

Figure 4. Electroretinograms of patients 1, 2, and 3. The rod-isolated responses were not recordable, and the amplitudes of 30-Hz flicker responses were reduced in all patients.

nal degeneration in the midperipheral retina associated with attenuated retinal vessels (Figure 2, D). The macular area was relatively spared. Fluorescein angiography disclosed diffuse hyperfluorescence in the posterior and midperiph- eral regions associated with patchy hypofluorescent areas along the vascular arcade (Figure 3, C). The scotopic ERG showed extinguished amplitudes bilaterally. A dark- adapted standard ERG (Figure 4) disclosed reduced am- plitudes of the a waves and extinguished amplitudes of the B b waves bilaterally. The amplitudes of the 30-Hz flicker ERG were reduced bilaterally.

COMMENT Arrestin is a photoreceptor-specific soluble protein that normally plays an important role in quenching the phototransduction cascade by inactivating phosphorylated-activated rhodopsin.5 The 1147delA mutation in the arrestin gene has been found as a fre- quent cause of Oguchi disease in the Japanese popula- tion. In this study, we found the same mutation in patients with autosomal recessive RP. No other pos- sible disease-causing mutation was found in the rho- dopsin, peripherin/RDS, and ROM1 genes in these C patients. The results suggest that variable expressivity Figure 3. A, The fluorescein angiogram of patient 1: A hypofluorescent area is produced by the mutation in the arrestin gene. due to chorioretinal atrophy is seen in the macular and pericentral regions. B, In our previous study on phenotypic characteris- The fluorescein angiogram of patient 2: A diffuse hyperfluorescent area in the tics of patients with Oguchi disease, we also found slight posterior portion of the eye is associated with hypofluorescent areas in the pericentral region. C, The fluorescein angiogram of patient 3: variability in clinical features in patients with the arres- 4 Hypofluorescent areas are distributed along the pericentral area in the diffuse tin 1147delA mutation. In particular, the presence of par- hyperfluorescent area in the posterior and midperipheral regions. tial chorioretinal degeneration in a patient with Oguchi disease led us to speculate that the arrestin gene might CASE 3 also be a candidate gene of RP. We therefore extended our study and found that a previously unexamined sib- A 72-year-old woman was referred to our clinic because ling (patient 1) of the patient with Oguchi disease (OG12) of RP. She had had night blindness and constriction of her had RP that was associated with the same mutation as visual field for 20 years. She noticed a gradual progression Oguchi disease. Further screening revealed the homo- of visual impairment. Her parents were first cousins (Fig- zygous 1147delA mutation in the arrestin gene in 2 ad- ure 1). Fundus examination showed diffuse pigmentary reti- ditional patients with RP. Phenotypic characteristics of

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©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 these 3 patients with the 1147delA mutation were also Accepted for publication October 29, 1997. variable in visual acuity, the distribution of pigmentary This study was supported in part by a grant from retinal degeneration, and the presence or absence of the the Research Committee on Chorioretinal Degenerations golden-yellow fundus reflex. The patients commonly and Optic Atrophy, the Ministry of Health and Welfare of showed partial chorioretinal atrophy, however, particu- the Japanese Government (Dr Nakazawa), Tokyo, and a larly along the vascular arcade, which was demon- grant-in-aid for scientific research from the Ministry of strated by fluorescein angiography (Figure 3). This re- Education, Science, and Culture of the Japanese Govern- gion is also the location in which partial chorioretinal ment (Dr Nakazawa, C-2-09671782), Tokyo. atrophy preferentially occurs in patients with Oguchi Reprints: Mitsuru Nakazawa, MD, Department of disease.4 Electrophysiologically, a pattern of rod- Ophthalmology, Tohoku University School of Medicine, predominant impairment was observed in these pa- 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan. tients. Although the degree of impairment in rods and cones was more severe in patients with RP than in those with Oguchi disease, the pattern of impairment was simi- REFERENCES lar among patients with the arrestin 1147delA mutation 4 (Figure 4 and Nakazawa et al ). As was found in our pre- 1. Dryja TP, Li T. Molecular genetics of retinitis pigmentosa. Hum Mol Genet. 1995; vious study,4 clinical expressions associated with the ar- 4:1739-1743. restin 1147delA mutation were distributed in Oguchi dis- 2. Fuchs S, Nakazawa M, Maw M, Tamai M, Oguchi Y, Gal A. A homozygous 1– base pair deletion in the arrestin gene is a frequent cause of Oguchi disease in ease, Oguchi disease with partial chorioretinal Japanese. Nat Genet. 1995;10:360-362. degeneration, and RP with or without the golden- 3. Yamanaka M. Histologic study of Oguchi’s disease. Am J Ophthalmol. 1969;68: yellow fundus reflex. It has been suggested that this vari- 19-26. ability may be a spectrum of phenotypes caused by a mu- 4. Nakazawa M, Wada Y, Fuchs S, Gal A, Tamai M. Oguchi disease: phenotypic char- tation in the arrestin gene. This could also explain the acteristics in patients associated with the frequent 1147delA mutation in the ar- restin gene. Retina. 1997;17:17-22. coexistence of patients with Oguchi disease and RP in 5. Ku¨hn H, Hall SW, Wilden U. Light induced binding of 48-kDa protein to photo- 3 the same family, although the exact mechanism of such receptor membranes is highly enhanced by phosphorylation of rhodopsin. FEBS a wide range of clinical features is unknown. Lett. 1984;176:473-478.

100 Years Ago in the ARCHIVES

A look at the past. . . ODEWALD records 3 cases of injury of the eye from a bird’s beak. The remarkable fact brought R out was that, although one would not con- sider such injuries antiseptic, recovery ensued even in the cases of severe and extensive injury.

Reference: Arch Ophthalmol. 1897; 26:308.

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