Autosomal Dominant Macular Degeneration Associated with 208Delg Mutation in the FSCN2 Gene

OPHTHALMIC MOLECULAR GENETICS

SECTION EDITOR: EDWIN M. STONE, MD, PhD Autosomal Dominant Macular Degeneration Associated With 208delG Mutation in the FSCN2 Gene

Yuko Wada, MD; Toshiaki Abe, MD; Toshitaka Itabashi, MD; Hajime Sato, MD; Miyuki Kawamura, MD; Makoto Tamai, MD

Objective: To assess the clinical and genetic character- different phenotypes, autosomal dominant retinitis pig- istics of 2 Japanese families with autosomal dominant mentosa and ADMD. macular degeneration (ADMD) associated with a 208delG mutation in the retinal fascin (FSCN2) gene. Conclusions: The 208delG mutation in the FSCN2 gene produces not only autosomal dominant retinitis pigmen- Design: Case reports with clinical findings and results tosa but also ADMD in the Japanese population. This mu- of fluorescein angiography, electroretinography, ki- tation is relatively common in Japanese patients with au- netic visual field testing, and DNA analysis. tosomal dominant retinal degeneration and showed clinical variability. Setting: University medical center. Clinical Relevance: Autosomal dominant retinitis pig- Results: The 208delG mutation in the FSCN2 gene was mentosa and ADMD can be caused by the same 208delG identified in 14 members of 4 Japanese families with au- mutation. We suggest that mutations in the FSCN2 gene tosomal dominant retinitis pigmentosa and in 5 mem- can lead to a spectrum of phenotypes. bers of 2 Japanese families with ADMD. The character- istic features associated with this mutation led to 2 Arch Ophthalmol. 2003;121:1613-1620

ACULAR DEGENERATION patients with ADRP (14 patients from 4 un- (MD) can have a domi- related families) have the identical 208delG nant or recessive in- mutation in the FSCN2 gene. FSCN2, a can- heritance pattern and didate gene for ADRP, is located on chro- shows clinical and ge- mosome 17q25 and plays an important role neticM heterogeneity. To date, 4 loci and 6 in photoreceptor disc formation. The clini- candidate genes for MD have been re- cal characteristics of the 14 patients from ported, and 10 loci and 28 candidate genes 4 families with the 208delG mutation were for retinitis pigmentosa (RP) have been those of typical RP.14 identified.1 Among these candidate genes, However, 1 patient had an atrophic the peripherin/RDS gene causes autoso- MD in addition to the pigmentary retinal de- mal dominant retinitis pigmentosa (ADRP) generation. This finding suggested the pos- and autosomal dominant macular degen- sibility that mutations in the FSCN2 gene eration (ADMD). Therefore, it was re- were related to not only ADRP but also ported that the Arg172Trp,2-4 Tyr258Stop,5 ADMD. Thereafter, 148 patients from un- and Gly167Asp6 mutations cause ADMD related families with ADRP and 54 pa- and that the Trp179Arg,7 Cys165Thr,8 tients from unrelated families with cone- Phe211Leu,8 and Asn244Lys9 mutations rod dystrophy or MD were screened to cause ADRP. These reports suggested that search for mutations in the FSCN2 gene. other candidate genes for RP caused other Fourteen patients from 4 unrelated fami- phenotypes, such as MD. lies with ADRP and 5 patients from 2 un- From the Department of In 2001, it was first reported that the related families with ADMD had the iden- Ophthalmology, Tohoku 12 University School of Medicine, human retinal fascin gene (FSCN2) was one tical 208delG mutation in the FSCN2 gene. Sendai, Japan. The authors of the causative genes for Japanese We describe herein the ocular findings as- have no relevant financial patients with ADRP. This and other sociated with the 208delG mutation in 2 of interest in this article. studies10-14 disclosed that about 3.0% of the these Japanese families with ADMD.

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12 I 1 2 I Normal Allele 12 1 X X II 2 II +/+ M/+

12 34XX5 XXX III 1 23 M/+ +/+ III M/+ +/+ M/+ 12XX 3 IV Deletion G M/+ +/+ 1 V T A CCT– A C A G C T G A

Figure 1. Pedigrees of 2 Japanese families with macular degeneration Mutant Allele associated with the 208delG mutation in the FSCN2 gene showing affected (solid symbols) and unaffected (open symbols) members. Squares indicate male; circles, female; X, individuals examined in this study; slash, deceased; arrow, proband; M, mutant allele; and plus sign, normal allele.

METHODS Figure 2. Results of nucleotide sequencing analysis of exon 1 in patient III:4 of family 1 showing the heterozygous 208delG mutation. The arrow indicates Genomic DNA samples isolated from 148 patients from unre- the position of the mutation. lated families with ADRP and from 54 patients from unrelated families with cone-rod dystrophy or MD were screened to search for mutations in the FSCN2 gene. One hundred control chro- quence. There was a deletion of nucleotide G at the mosomes from 50 normal subjects were further screened for complementary DNA position 208, and this was desig- mutations of this gene. Informed consent was obtained from nated as a 208delG mutation in the FSCN2 gene all patients before their entry into this study. (Figure 2). The nonaffected members did not have this The sequences from exon 1 to exon 5 of the FSCN2 gene mutation, and this mutation cosegregated with the phe- were amplified by polymerase chain reaction. Nine sets of oli- notype of MD (Figure 1). We further screened our pa- gonucleotide primer pairs were used to cover the extent of these tients for mutations in the peripherin/RDS, CRX, and sequences.12 Products of the polymerase chain reaction were GUCY2D genes, and no mutation was detected. We also directly sequenced in the forward and reverse directions on an confirmed that the 208delG mutation was not present in ABI sequencer (model 3100; Applied Biosystems, Foster City, 100 normal control chromosomes. Calif). The clinical features of the 4 Japanese families with ADRP associated with the 208delG mutation have already been reported.12 We present herein our findings on the 5 patients from REPORT OF CASES 2 Japanese families with ADMD. The heterozygous 208delG mutation in the FSCN2 gene was identified in all affected mem- FAMILY 1, PATIENT III:4 bers from the 2 families (Figure 1). Ophthalmic examinations included best-corrected visual The proband, a 62-year-old man, had a gradual progres- acuity, kinetic visual field examination, slitlamp biomicros- sion of visual impairment, photophobia, and constric- copy, fundus examination, fluorescein angiography, and elec- tion of the visual field during his 40s. In 1992, at age 52, troretinography. Ophthalmoscopic findings were recorded by he visited our clinic to have a detailed assessment of his color fundus photography. Kinetic visual field examinations were eyes. His visual acuity was corrected to 0.70 OD with a performed on the Goldmann perimetry with the V-4-e, I-4-e, I-3-e, and I-2-e targets. 2.0 diopter (D) sphere and to 0.06 OS with a 1.0 D sphere. Electroretinograms (ERGs) were recorded under con- Slitlamp biomicroscopic examination showed nor- trolled conditions that conformed to the standards of the In- mal-appearing cornea, anterior chamber, iris, lens, and ternational Society of Clinical Electrophysiology of Vision.15 vitreous in both eyes. Fundus examination showed the Briefly, photopic ERGs were elicited by a single flash or a 30-Hz mottled appearance of retinal pigment epithelium (RPE) flicker stimulus of red light under light-adapted conditions in the posterior pole bilaterally (Figure 3A). Fluores- (cone-isolated responses); a dim blue flash under dark- cein angiography disclosed diffuse hyperfluorescence adapted conditions (30 minutes) was used for the rod-isolated around the macula in the right eye and oval and round ERGs (rod-isolated responses); and a bright white flash (in- hyperfluorescent lesions in the posterior pole of the left tensity of 1.69 candelas/m2 per second) under dark-adapted con- eye (Figure 4A). ditions was used to elicit the mixed cone-rod responses. The means±SDs of the amplitudes of the ERGs of the normal sub- The rod-isolated, photopic, mixed cone-rod, and jects in our laboratory were: rod-isolated b-wave, 230.1±51.2 30-Hz flicker ERGs were within the normal range µV; photopic a-wave, 57.2±17.1 µV; photopic b-wave, (Figure 5). The patient could not identify the numbers 110.3±22.6 µV; mixed a-wave, 376.3±49.4 µV; mixed b- on the Ishihara plates. wave, 560.2±72.9 µV; and 30-Hz flicker, 127.5±24.1 µV. He experienced an accelerated deterioration of central visual acuity after his first visit in 1992 at age 52. In RESULTS 2001, his visual acuity had decreased to counting fin- gers in both eyes. Fundus examination at this time showed The 5 affected members from the 2 families with ADMD bilateral atrophic MD, a mottled appearance of the RPE, (Figure 1) had an identical abnormal nucleotide se- which appeared to have progressed since his first visit,

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C D

Figure 3. Fundus photographs of symptomatic patients. A, Patient III:4 of family 1 at age 52 years. The mottled appearance of retinal pigment epithelium in the posterior pole can be seen. B, Same patient at age 62. Atrophic macular degeneration has progressed during the 10 years. C, Patient III:1 of family 2 at age 13 years showing atrophic degeneration in the posterior pole without attenuation of the retinal vessels. D, Same patient at age 23. Sharply demarcated atrophic degeneration with pigmentation can be seen, which has progressed during the 10 years.

and diffuse retinal mottling in the midperipheral areas erally (Figure 6A). Fluorescein angiography disclosed (Figure 3B). Fluorescein angiography showed oval- granular hyperfluorescence from the posterior pole to the shaped hyperfluorescence with hypofluorescence within midperipheral areas in both eyes. The a- and b-wave am- the lesions (Figure 4B). Kinetic visual field testing showed plitudes of the mixed cone-rod ERGs were normal, al- only small residual islands of visual field remaining in though the oscillatory potentials were reduced. The rod- the paracentral region bilaterally. Kinetic visual field test- isolated, photopic, and 30-Hz flicker ERGs were of normal ing had low reliability because of his age, poor visual acu- amplitude (Figure 5). Goldmann kinetic visual field test- ity, and poor fixation. The ERG examinations in 2001 ing showed constricted visual fields for the I-3-e and I-2-e also showed normal rod-isolated, mixed cone-rod re- targets (Figure 7A). Color vision was normal on the sponse, photopic, and 30-Hz flicker ERGs. panel D-15 test.

FAMILY 1, PATIENT IV:2 FAMILY 2, PATIENT III:1

Patient IV:2, the 37-year-old son of patient III:4, had no A 26-year-old man first manifested a decrease of visual subjective impairment in his central, peripheral, or night acuity when he was an elementary schoolchild. When he vision. His visual acuity was 1.0 OS with a –1.50 to was 8 years old, he was diagnosed as having retinal de- 2.50ϫ 30° refraction and 1.2 OD with a −1.50 to generation. In 1990, he visited our clinic to have a de- 1.25ϫ150° refraction. Slitlamp biomicroscopic exami- tailed assessment of his eyes. His visual acuity was cor- nation showed normal-appearing cornea, anterior cham- rected to 0.08 OD with a −1.00 D sphere and to 0.80 OS ber, iris, and lens in both eyes. Fundus examination with a –0.75ϫ150° refraction. Slitlamp biomicroscopic showed a mottled appearance of the RPE, yellowish de- examination showed normal-appearing cornea, ante- posits in the macula, and an irregular ring reflex bilat- rior chamber, iris, lens, and vitreous in both eyes.

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C D

Figure 4. Fluorescein angiograms of symptomatic patients. A, Patient III:4 of family 1 at age 52 years. Diffuse hyperfluorescence around the macula can be seen. B, Same patient at age 62 showing oval hyperfluorescent lesions with hypofluorescence within the lesions. C, Patient III:1 of family 2 at age 13 years shows round hyperfluorescent lesions with hypofluorescence within. D, Same patient at age 23 showing enlargement of hypofluorescent areas, which demonstrates the progression of chorioretinal atrophy during the 10 years.

Fundus examination at age 13 showed mildly de- 2001, his visual acuity was corrected to 0.2 OD with a marcated, atrophic MD associated with diffuse mottling –2.5 D sphere in both eyes. Fundus examination at this of the retina in the midperipheral area in both eyes (Fig- time disclosed atrophic MD with pigmentation in both ure 3C). Fluorescein angiography demonstrated round- eyes that had progressed since 1990 (Figure 3D). Fluo- shaped hyperfluorescence associated with hypofluores- rescein angiography disclosed round hyperfluorescent le- cence within the lesions (Figure 4C). The hyperfluorescent sions associated with an enlargement of the hypofluo- lesions corresponded to the atrophy of the RPE, and the rescent areas in the posterior pole of both eyes (Figure hypofluorescent lesions corresponded to the chorioreti- 4D). Kinetic visual field testing showed absolute scoto- nal atrophy. mas with relatively well preserved peripheral areas (Fig- The rod-isolated response and photopic ERGs ure 7B). The ERG examinations in 1999 demonstrated were within the normal range. The amplitudes of the no remarkable changes. mixed cone-rod b-waves were reduced to 75% of the normal amplitude in both eyes (percentage reduction FAMILY 2, PATIENT III:3 below the normal mean, 560.2 µV), and the oscillatory potentials were also reduced. The 30-Hz flicker The 15-year-old younger sister of patient III:1 had no im- responses were mildly reduced (61.3 µV OD and 65.3 pairment of visual acuity or night vision. Because her older µV OS; controls, 127.5±24.1 µV; Figure 5). Color brother (III:1) was diagnosed as having MD in our clinic, vision testing showed a tritanopic pattern in the right she also visited our clinic at age 8 years. Her best cor- eye and a normal pattern in the left eye on the panel rected visual acuity was 0.9 OD with a 1.0 to 0.5ϫ150° D-15 test. refraction and 0.9 OS with a –0.5 D sphere. Slitlamp bio- He experienced an accelerated deterioration of cen- microscopic findings in the cornea, anterior chamber, iris, tral visual acuity after his first visit in 1990 at age 13. In and lens were normal in both eyes.

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R R R R L Normal L L 200 µV L µ 10 ms 100 V 20 ms 200 µV R R R R III:4 20 ms L L L (Family 1) L

R R IV:2 R R (Family 1) L L L L

R R L III:1 R R (Family 2) L L L

R R III:3 R L R (Family 2) L L L

Figure 5. Electroretinograms (ERGs) of 4 affected members. Patient IV:2 of family 1 and patients III:1 and III:3 of family 2 show reduced oscillatory potentials. Patient III:1 shows mildly reduced b-waves of the mixed cone-rod ERG and mildly reduced 30-Hz flicker ERGs. Patient III:3 shows mildly reduced a- and b-waves in the mixed flash ERG. Patients are described in detail in the “Report of Cases” section of the article. R indicates right eye; L, left eye.

Fundus examination at age 8 showed a mottled ap- COMMENT pearance of the RPE in the posterior pole. The rod- isolated ERGs and 30-Hz flicker ERGs were within the normal range. The amplitude of the a-wave of the mixed Macular degeneration is characterized by a reduction of cone-rod ERGs was reduced to 64% OD and to 79% OS, visual acuity, abnormal color vision, and a central sco- and the b-wave was reduced to 85% OD and was within toma. The inheritance pattern for MD can be autosomal the normal range in the left eye. The oscillatory poten- dominant or recessive. Recent molecular genetic analy- tials were also reduced (Figure 5). ses have shown that inherited retinal degeneration has In 2001, her visual acuity was corrected to 0.7 OD with allelic or nonallelic heterogeneity and that the pheno- a −1.5 D sphere and to 1.0 OS with a –1.5 D sphere. Fun- type depends on the type of mutation (eg, mutations of dus examination showed tortuous vessels, reddish optic peripherin/RDS and ABCA4 genes can lead to MD and discs, a mottled appearance of the RPE in both eyes, and RP).16-18 Also, mutations in the rhodopsin and bPDE pigmentation in the left macula (Figure 6B). The atrophic genes have been implicated in not only congenital sta- lesions had slightly enlarged since she first visited our clinic. tionary night blindness but also RP.19-22 On the other Goldmann kinetic visual field testing showed a slight hand, an identical 1147delA mutation in the arrestin peripheral constriction with the V-4-e and I-4-e targets, gene is the cause of not only Oguchi disease but also au- although she did not have a paracentral and central sco- tosomal recessive RP.23-25 These findings indicate that toma (Figure 7C). some other candidate genes for RP will cause other phenotypes. In this study, we focused on the relationship FAMILY 2, PATIENT II:2 between ADMD and mutation of the FSCN2 gene in the Japanese population. The 50-year-old mother of the family 2 patients had no Retinal fascin (FSCN2) is a photoreceptor-specific visual complaints. Her visual acuity was corrected to 1.0 gene located on chromosome 17q25 and is a member of OD with a –1.5 D sphere and to 1.0 OS with a –1.5 D the fascin gene family. It encodes 516 amino acids and sphere. Slitlamp biomicroscopic examination showed nor- is responsible for the assemblage of actin-based struc- mal-appearing cornea, anterior chamber, iris, lens, and tures of the connecting cilium plasma membrane and is vitreous in each eye. Fundus examination disclosed tor- involved in photoreceptor disc formation.10-14 An earlier tuosity of retinal vessels and mild atrophy of the RPE in study14 showed that a 208delG mutation was the cause the posterior pole and midperipheral retina, although the of ADRP in the Japanese population. Interestingly, some degenerative changes of the RPE and macula are not ob- variation was found in the clinical features of patients with vious in the fundus photograph (Figure 6C). Visual field this mutation. In particular, the presence of a sharply de- testing showed a mild peripheral constriction with the marcated MD in 1 patient with ADRP led to the sugges- V-4-e, I-4-e, and I-2-e targets (Figure 7D). tion that the FSCN2 gene might also be a candidate gene

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Figure 6. Fundus photographs of asymptomatic patients. A, Patient IV:2 of family 1 at age 37 years. The retinal pigment epithelium (RPE) is mottled, and yellowish deposits in the macula and an irregular ring reflex can be seen. B, Patient III:3 of family 2 at age 15 years shows the mottled appearance of RPE, tortuous vessels, and a reddish-colored optic disc. C, Patient II:2 of family 2 at age 50 years. Tortuosity of the retinal vessels is observed.

for MD. These study findings were extended herein, and phy and cone dystrophy, such as peripherin/RDS, CRX, we found that 5 affected members from 2 unrelated fami- and GUCY2D genes, to search for additional mutations. lies with MD had a mutation in the FSCN2 gene. The results did not show any disease-causing mutation The clinical features produced by this mutation in in these 3 genes; therefore, mutations in at least these genes the 5 affected members showed extreme variation in se- are unlikely to be related to the pathogenesis of MD in verity. The asymptomatic members had only slight at- our patients. However, further molecular genetic analy- rophy of the RPE, or mildly constricted visual fields, and sis is needed to eliminate other possibilities. an irregular ring reflex in the macula. The symptomatic Taken together with previous results, we conclude patients had decreased visual acuity, central scotoma, se- that the 208delG mutation in the FSCN2 gene is respon- verely constricted visual field, atrophy of the RPE, and sible for not only ADRP but also ADMD. However, we central retinal degeneration. cannot explain the variability of expressivity of the To examine the possibility of a digenic inheritance, 208delG mutation in the FSCN2 gene. This mutation in we screened other candidate genes for macular dystro- the FSCN2 gene and the 1147delA mutation in the ar-

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Figure 7. Results of Goldmann visual field testing of patient IV:2 of family 1 (A), patient III:1 of family 2 (B), patient III:3 of family 2 (C), and patient II:2 of family 2 (D). Patient III:1 (B) shows an absolute scotoma with a relatively well preserved peripheral area. Patients are described in detail in the “Report of Cases” section of the article. L indicates left eye; R, right eye.

restin gene have been found only in Japanese patients. A-14704044 from the Ministry of Education, Science, and Although the Pro23His and Pro347Leu mutations in the Culture (Dr Wada), Japanese government, Tokyo, Japan. rhodopsin gene and the Arg677Ter mutation in the RP1 Corresponding author and reprints: Yuko Wada, MD, gene are representative mutations for ADRP, they are not Department of Ophthalmology, Tohoku University School found or are very rare in Japanese patients with ADRP. of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-77, Ja- Moreover, we found 4 polymorphisms in exon 1 pan (e-mail: [email protected]). (Thr211Thr, Leu238Leu, Thr244Thr, and Pro246Pro) of the FSCN2 gene, 2 of which (Thr211Thr and Pro246Pro) were previously reported,14 and the others were found REFERENCES only in Japanese patients. These findings suggest that the kind and frequency 1. RetNet. Cloned and/or mapped genes causing retinal diseases. Available at: http: of mutations depend on the ethnic population. The phe- //www.sph.uth.tmc.edu/RetNet/disease.htm. Accessed April 12, 2002. notypic differences (ADMD and ADRP) induced by the 2. Wells J, Wroblewski J, Keen J, et al. Mutations in the human retinal degeneration slow (RDS) gene can cause either retinitis pigmentosa or macular dystro- 208delG mutation in the FSCN2 gene were probably due phy. Nat Genet. 1993;3:213-218. to the functional loss of 1 allele, resulting in haploinsuf- 3. Wroblewski JJ, Wells JA III, Eckstein A, et al. Macular dystrophy associated with ficiency. Further molecular biological analysis, such as mutations at codon 172 in the human retinal degeneration slow gene. Ophthal- transgenic experiments or gene expression studies, will mology. 1994;101:12-22. 4. Nakazawa M, Wada Y, Tamai M. Macular dystrophy associated with monogenic augment our understanding of the mechanism of pho- Arg172Trp mutation of the peripherin/RDS gene in a Japanese family. Retina. toreceptor degeneration. 1995;15:518-523. In conclusion, we have identified a heterozygous 5. Felbor U, Schilling H, Weber BH. Adult vitelliform macular dystrophy is fre- 208delG mutation in the FSCN2 gene among Japanese quently associated with mutations in the peripherin/RDS gene. Hum Mutat. 1997; families with not only ADRP but also ADMD. We sug- 10:301-309. 6. Kemp CM, Jacobson SG, Cideciyan AV, Kimura AE, Sheffield VC, Stone EM. RDS gest that the 208delG mutation may be a relatively com- gene mutations causing retinitis pigmentosa or macular degeneration lead to the mon cause of inherited retinal degeneration in Japanese same abnormality in photoreceptor function. Invest Ophthalmol Vis Sci. 1994; patients. Our study provides evidence that a mutation in 35:3154-3162. the FSCN2 gene is related, in part at least, to the patho- 7. Bareil C, Delague V, Arnaud B, Demaille J, Hamel C, Claustres M. W179R: a novel missense mutation in the peripherin/RDS gene in a family with autosomal domi- genesis of MD. nant retinitis pigmentosa. Hum Mutat. 2000;15:583-584. 8. Souied EH, Rozet JM, Gerber S, et al. Two novel missense mutations in the pe- Submitted for publication July 12, 2002; final revision re- ripherin/RDS gene in two unrelated French patients with autosomal dominant ceived February 18, 2003; accepted June 3, 2003. retinitis pigmentosa. Eur J Ophthalmol. 1998;8:98-101. This study was supported in part by a grant from the 9. Nakazawa M, Kikawa E, Kamio K, Chida Y, Shiono T, Tamai M. Ocular findings in patients with autosomal dominant retinitis pigmentosa and transversion muta- Research Committee on Chorioretinal Degeneration and tion in codon 244 (Asn244Lys) of the peripherin/RDS gene. Arch Ophthalmol. Optic Atrophy, Ministry of Health, Labour, and Welfare 1994;112:1567-1573. (Dr Tamai) and by Grant-in-Aid for Scientific Research 10. Bardien-Kruger S, Greenberg J, Tubb B, et al. Refinement of the RP17 locus for

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Flying Fundus. Created by Patrick J. Saine, MEd, CRA, Dartmouth-Hitchcock Medical Center, Lebanon, NH.

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