New Mutation, P575L, in the GUCY2D Gene in a Family with Autosomal Dominant Progressive Cone Degeneration

OPHTHALMIC MOLECULAR GENETICS New Mutation, P575L, in the GUCY2D Gene in a Family With Autosomal Dominant Progressive Cone Degeneration

Kent W. Small, MD; Rosamaria Silva-Garcia, MD; Nitin Udar, PhD; Eddy V. Nguyen, MD; John R. Heckenlively, MD

Objectives: To clinically characterize the retinal ab- Conclusions:Inadditiontofindingapreviouslyundescribed normalities and identify the mutation causing an auto- mutation in GUCY2D, 2 of the family members who were somal dominant cone degeneration in an African Ameri- thought to be unaffected through routine clinical examina- can family. tions also had this mutation. These findings suggest that autosomal dominant cone degeneration in this family dem- Methods: Clinical characterization of family members onstrated age-dependent penetrance, which appears incom- using fundus photography, fluorescein angiography, and plete. This is the first African American family reported with electrophysiological testing. Standard molecular ge- a mutation in GUCY2D. Because the disease in this family netic methods were used, including segregation analy- and the one we previously described is primarily a cone de- sis and DNA sequencing of candidate genes. Genetic mu- generation, this disease should be more properly classified tation screening was performed in 20 individuals: 10 as cone degeneration and be called cone degeneration 2. clinically unaffected and 10 affected. Clinical Relevance: This study helps to expand the phe- Results: The affected family members had findings con- notype of the disease and help clinicians identify pa- sistent with a primary cone degeneration. A novel mu- tients with cone degenerations. tation, P575L, was found in exon 8 of the GUCY2D gene in 12 members of this family. Arch Ophthalmol. 2008;126(3):397-403

ONE DYSTROPHIES ARE A mal recessive, or X-linked recessive trait heterogenous group of with the most common variant being au- retinal disorders charac- tosomal dominant.1-31 terized by widespread loss In the past decade, much progress has of cone function with rela- been made in characterizing the genetics of tiveC preservation of rod function. The clas- cone dystrophies. Several genetic loci have sic triad of symptoms is photophobia, dys- been identified in association with cone and chromatopsia, and decreased central vision. cone-rod dystrophies, including peripherin/ Peripheral visual fields and night vision are the human retinal degeneration slow gene typically preserved. Color vision is usu- (RDS), guanylate cyclase activator 1A gene ally impaired early in the disease course (GUCA1A), and guanylate cyclase 2D gene with elevation of protan, deutan, or tritan (GUCY2D [Crx]). Other cone and cone- thresholds. Funduscopy results can vary rod dystrophy loci have been mapped to from mild pigment granularity to a dis- chromosomes 6q, 18q, 19q, and 17p.32-59 Author Affiliations: crete atrophic lesion in the center of the CORD5, which is an autosomal dominant, Cedars-Sinai Medical Center macula. Electrophysiologic testing is almost pure cone degeneration, was mapped (Drs Small and Silva-Garcia); important to confirm the diagnosis. Perti- to chromosome 17p13-12 by Small et al and Molecular Insight LLC nent electroretinogram (ERG) character- later found to be caused by mutations in (Drs Small, Silva-Garcia, and istics include a reduction in the single- GUCY2D41-50; GUCY2D mutations were ini- Udar); and University of flash photopic and 30-Hz flicker response. tially described in the autosomal recessive California at Los Angeles 48,49 (Dr Nguyen), Los Angeles, The rod-isolated responses are normal in disease, Leber congenital anaurosis. We California; and Department of the early stages; however, as the disease describe an African American family with Ophthalmology, University of progresses, rod function may also be slightly autosomal dominant cone degeneration Michigan, Ann Arbor impaired. Cone degeneration can be inher- CORD5 with a previously undescribed mu- (Dr Heckenlively). ited as an autosomal dominant, autoso- tation in GUCY2D.

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©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 Genetyping with microsatellite markers was performed as described by Small et al41 to define the minimal candidate region. New polymorphic markers were identified by analyzing sequences from clones (GenBank AD005695). Flanking primers were designed using Primer 3 (Broad Institute, Cam- 2001 2000 bridge, Massachusetts; http://www-genome.wi.mit.edu) and ana- lyzed for being polymorphic by genotyping a total of 12 controls. The previously mentioned clones were aligned using the pub- lic National Center for Biotechnology Information database 1111 1008 1009 1003 1002 1010 1004 1006 1007 1000 (Bethesda, Maryland; http://www.ncbi.nlm.nit.gov) and Cel- era (Rockville, Maryland; http://www.celera.com). We developed the following markers, which are deposited at the GDB Human Genome Database (http://www.gdb.org): CORD5NU8 105 101 104 103 106 107 110 108 117 115 119 116 120 117 (GDB No. 11505481), CORD5NU12 (GDB No. 11505496), CORD5NU15 (GDB No. 11505484), CORD5NU17 (GDB No. 9001 11505497), CORD5NU19 (GDB No. 11505486), CORD5NU20 (GDB No. 11505487), CORD5NU26 (GDB No. 11505488), Figure 1. Pedigree of family showing individuals with and without autosomal CORD5NU34 (GDB No. 11505489), CORD5NU35 (GDB dominant progressive cone degeneration. No. 11505498), CORD5NU37 (GDB No. 11505491), and CORD5NU38 (GDB No. 11505492). For DNA sequencing of the candidate genes, primers were METHODS synthesized more than 20 base pairs internal to the intronic region. After polymerase chain reaction amplification using pa- CLINICAL EXAMINATION tient and control DNA, the products were separated on aga- rose gel, 2%. The bands were cut from the gel and purified using Qiagen QIAquick PCR Purification Kit (Qiagen, Valencia, Cali- Clinical data collected included medical and ocular histories, fornia). The purified product was used for direct sequencing family history with pedigree, and external and slitlamp exami- using Thermo Sequenase Cycle Sequencing Kit (USB Corp, nation, refraction, and indirect and direct ophthalmoscopy find- Cleveland, Ohio). The sequencing reactions were separated on ings. Best-corrected Snellen visual acuities were obtained. Ex- an acrylamide, 6%, 7-M urea sequencing gel in 1ϫ Tris/borate/ aminations of 20 participants were performed in the EDTA buffer at 80 W constant power on a Biorad DNA se- ophthalmology office or at the participants’ homes. quencing apparatus (Bio-Rad Laboratories, Hercules, Califor- nia). Mutation screening for the P575L mutation was carried ELECTROPHYSIOLOGY TESTING out by amplifying exon 8 from individual DNA samples.

The ERGs were performed on a full-field (Ganzfeld) combina- tion, single flash–averaged unit on 5 participants. Our normal RESULTS laboratory values and analyses of data for age and sex effects have been previously determined. The standard International Society of Clinical Electrophysiology in Vision protocol was fol- REPORT OF CASES lowed.24,25 A 2-channel recorder was used for electrooculography testing. The maximum response in the light was divided Case 1 by the minimum response in the dark and multiplied by 100 and expressed as a percentage (Arden ratio). Case 1 (#116) was examined at the age of 22 years and The final rod threshold was determined by dark adapting was subsequently seen at her home in 1995 at age 38 years. the patient for 45 minutes and then testing the threshold of light She had had seizures since the age of 12 years. Her medi- perception at 11° above fixation with a Goldmann-Weekers dark cal history was otherwise unremarkable except for vi- adaptometer. A Nagel anomaloscope was used for color vision screening. Goldmann visual field tests, fluorescein angiogra- sual problems. Photophobia and decreased visual acu- phy, and fundus photography were performed in the standard ity began at 7 years of age. At age 22 years, her visual acuity manner on 4 members of the family. was 20/200 OD and 20/300 OS. Slitlamp examination de- tected no abnormalities and her intraocular pressure lev- GENETIC ANALYSIS els were normal. Funduscopy revealed a bilaterally sym- metrical central area of macular retinal pigment epithelium We ascertained a family of 4 generations with cone degenera- (RPE) atrophy (Figure 2A). The transmission defect vis- tion. The family is African American and comprises 24 living ible on fluorescein angiography corresponded to the drop- individuals (Figure 1). The inheritance pattern of the cone- out of the macular RPE (Figure 2B). There was no evi- rod degeneration phenotype in this family was consistent with dence of choroidal hypofluorescence or “silent choroid.” an autosomal dominant trait. Nineteen individuals from the fam- The photopic ERG was unrecordable (Figure 3). The ily were examined and characterized by the criteria previously scotopic ERG and the dark-adaptation final rod thresh- 51 described for CORD5. old results were normal. The electrooculography re- We obtained institutional review board approval and volun- sults were unreliable owing to poor central fixation. On tary informed consent from all participating individuals before en- rolling them in the study. Blood was obtained by venipuncture for reexamination at age 38 years, the participant’s near vi- DNA analysis from 20 participants. The DNA was extracted using sual acuity was J16 OU; fundus examination revealed pig- the Puregene protocol (Gentra Systems, Minneapolis, Minnesota). mentary clumps, but otherwise there was no significant The family’s pedigree (Figure 1) was constructed using Cyrillic soft- change from her prior examination. Color vision testing ware (Cherwell Scientific Inc, Oxford, England). with Ishihara plates was 0/14 OU.

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Figure 2. Case 1 (#116). A, Fundus photograph shows what appears to be a diffuse area of macular retinal pigment epithelium irregularity. At 22 years, she had a visual acuity of 20/200 OD and 20/300 OS. B, Fluorescein angiogram shows a loss of the macular retinal pigment epithelium, which was not as apparent on clinical examination or fundus photography, suggesting a milder form of the disease.

Case 2

Case 105 Blink The cousin of case 1 (#108) was examined at 32 years of response Blink age in 1980 and at 47 years in 1995. She had had sei- Case 116 response Case 101 zures since the age of 7 months and was mentally re- Case 1002 tarded. Her medical history was otherwise unremark- Case 1006 able except for visual problems. The family history was 100 µV 100 µV 200 µV 200 µV negative for seizures, except for case 1, and was nega- 20 ms 20 ms 20 ms 20 ms tive for mental retardation. She had had decreased visual acuity since the age of Figure 3. Standardized International Society for Clinical Electrophysiology of 7 years. Visual acuity was unobtainable in her right eye Vision electroretinogram for representative family members with dominant cone dystrophy. Case 6 (#1002) shows a better photopic electroretinogram owing to poor cooperation and 20/80 OS. Slitlamp ex- compared with that of her sibling (b-wave amplitude, 75 uV), which is 50% amination revealed no abnormalities. The macular area of normal mean age match value. The photopic implicit time was 5 had a granular appearance with circular RPE atrophy. milliseconds longer than normal (32 [SD, 1] milliseconds). Electroretinogram and visual field testing were not possible owing to the patient’s poor cooperation. ography revealed hyperfluorescence of a window defect in the area of the macular RPE loss. The photopic ERG Case 3 was nearly extinguished, and the flicker fusion test revealed an abnormal amplitude but was recordable at 60 The mother of case 1 (#1006) was examined at ages 54 flashes/s OU (Figure 3). The scotopic ERG and the dark- and 69 years in 1980 and 1995. Her medical history was adaptation final rod threshold results were normal. Color unremarkable except for visual problems. vision testing with a Nagel anomaloscope revealed an ab- Funduscopy performed when she was aged 54 years normally wide equation with a protanomalous axis and showed a well-demarcated macular lesion with atrophy a severe luminosity loss. The Goldmann visual field re- of the RPE. The photopic ERG was unrecordable and the sults were within normal limits except for a central sco- scotopic ERG had normal amplitudes with a slightly pro- toma. On examination at 33 years, his corrected visual longed implicit time (Figure 3). On examination at 69 acuity was 20/200 OD and 20/100 OS. His fundus ex- years, her near visual acuity with correction was J16 OU. amination results were unchanged. Color vision testing Color vision examination results with Ishihara plates was results with Ishihara plates was 0/14 OU. 0/14 OU. Case 5 Case 4 Case 5 (#101) is the sister of case 4. Her medical history Case 4 (#105) was examined at ages 21 and 38 years and was unremarkable except for visual problems. She was at home once when he was aged 33 years. His medical examined at ages 27 and 39 years. history was unremarkable except for visual problems, On examination at 27 years, her visual acuity was 20/ which surfaced during his teenage years. 200 OD and 20/300 OS. Funduscopy showed a pattern On examination at age 21 years, his visual acuity with- very similar to case 4, with macular RPE atrophy out correction was 20/400 OU. Funduscopy showed an (Figure 4A). Fluorescein angiography demonstrated hy- area of discrete macular RPE atrophy. Fluorescein angi- perfluorescence in the macular region (Figure 4B). The

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Figure 4. Case 5 (#101). A, Fundus photograph shows mild-appearing macular retinal pigment epithelium changes. The patient was a 27-year-old woman with a visual acuity of 20/200 OD and 20/300 OS. B, Fluorescein angiogram shows a central window defect indicating retinal pigment epithelium atrophy, suggesting a slightly milder form of autosomal dominant progressive cone degeneration.

A B

Figure 5. Case 6 (#1002; the mother of patients #101 and #105). A, Fundus photograph shows discrete, circular, macular retinal pigment epithelium atrophy. The patient was aged 48 years and her visual acuity was 20/100 OD and 20/200 OS. B, Fluorescein angiogram shows a large central area of retinal pigment epithelium and choriocapillaris atrophy.

photopic ERG and the flicker fusion test results were ab- visual problems, which started at the age of 33 years. She normal in each eye. The scotopic ERG and dark- was examined at ages 48 and 60 years. adaptation final rod threshold results were normal. Color On examination at 48 years, her visual acuity was 20/ vision testing with the Nagel anomaloscope revealed an 100 OD and 20/200 OS. Funduscopy showed macular abnormality identical to that seen in case 4. The Gold- RPE atrophy with a sharp border (Figure 5A). Fluo- mann visual fields were within normal limits except for a rescein angiography allowed visualization of the cho- central scotoma. On examination at age 39 years, the pa- roidal vessels in the area of macular RPE atrophy tient’s uncorrected visual acuity was 20/400 (20/200 pin- (Figure 5B). The photopic ERG revealed subnormal hole) OD and 20/400 (20/200 pinhole) OS. Fundus ex- amplitude in each eye. The scotopic ERG and the dark- amination revealed central atrophy, which demonstrated adaptation final rod threshold results were normal large choroidal vessels in each eye. She missed all 14 plates (Figure 3). Color vision testing with the Nagel anoma- in each eye in the Ishihara color vision testing. loscope showed an abnormality identical to that seen in cases 4 and 5. The Goldmann visual fields were signifi- Case 6 cant for a central scotoma in each eye. On examination at age 60 years, her visual acuity was 20/200 pinhole NI Case 6 (#1002), aged 47 years, is the mother of cases 4 OD and 20/200 (20/300 pinhole) OS. Fundus examina- and 5. Her medical history was unremarkable except for tion revealed a discrete macular atrophy in each eye,

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C A G C A C A T A G C T A T C C G C C A A G C A A C C A A G A C G

G T C G T G T A T C G A T A G G C G G G T C G T T G G T T C T G C

Q H I A I R P A T K T

Figure 6. Genomic structure of GUCY2D showing the mutation P575L in a family with autosomal dominant progressive cone degeneration.

which appeared unchanged from the patient’s previous The heterozygous mutation in exon 8, C1797T, reexamination. sulted in a missense mutation in codon 575 (P575L), which segregated with all affected family members. There Case 7 were 2 unaffected family members who were found to have the mutation as well, suggesting incomplete pen- This individual (#110) was examined during a home visit etrance. This is the second report of apparent incom- at age 29 years. At that time, she had no visual complete penetrance with GUCY2D mutations.41,51 Pen- plaints and specifically denied photophobia. Her visual etrance is the probability of expressing the disease given acuity without correction using a near vision card was that a mutation is present, and the degree of penetrance 20/15 OD and 20/20 OS. She correctly identified 15 of depends on the extent and type of clinical evaluations 15 pseudoisochrome color plates. Dilated funduscopic performed on the participants. Penetrance can also be age examination results were normal. She was found to have dependent, as seems to be the case in this family as well the P575L mutation. as our previous white CORD5 family. The first individual exhibiting reduced penetrance Case 8 (#9001) was a 14-year-old girl with no symptoms of photophobia, hemeralopia, or decreased visual acuity. Her This patient (#9001) was examined during a home vision was 20/20 OU, and her fundus examination re- visit at the age of 14 years. She had no visual com- sults were unremarkable. She may have been too young plaints and specifically denied photophobia. Her to have any clinical manifestations yet. The second un- uncorrected visual acuity with a near card was 20/20 affected individual (#110) was a 29-year-old woman with OD and 20/20 OS. She correctly identified 13 of 15 a visual acuity of 20/15 OD and 20/20 OS. She had no pseudoisochrome color plates. Dilated funduscopic symptoms and no clinical evidence of cone degenera- examination results were normal. She was found to tion on ophthalmoscopy. Because of previous reports have the P575L mutation. documenting age-dependent penetrance in CORD5,itis possible that these individuals will manifest the disease phenotype at a later age, though it is unlikely for the 29- GENETIC ANALYSIS year-old woman (#110). Previous cone degeneration studies by Small et al41 have documented an individual who Genetic mutation screening was performed on 10 clini- was symptomatically normal until age 51 years. This study cally unaffected and 10 affected individuals. A novel mu- estimated the age-dependent penetrance to be 60% in the tation, P575L, was found in exon 8 of the GUCY2D gene first decade of life, 80% within the first 2 decades of life, in 14 members of this family (Figure 6). Two of the fam- and 95% thereafter.41 If one defines the disease and its ily members (#9001 and #110) who were thought to be penetrance on routine clinical examination, as is typical clinically unaffected by examinations also carried this mu- (without additional testing), these 2 family members tation. We tested 244 control chromosomes and found (#9001 and #110) likely represent incomplete pen- no such base-pair changes. etrance. Some geneticists make the case, rightfully, that incomplete penetrance is the extreme form of variable COMMENT expressivity. In this study, most of the clinically affected family members felt they were visually impaired We identified an African American family with autoso- all of their lives or developed symptoms at ages 8 to 16 mal dominant cone degeneration. This is the first clini- years. Based on our previously described CORD5 fam- cal and genetic characterization of cone degeneration in ily, participants who were asymptomatic had normal ERG an African American family and it is the first report of results as well. When performing genetic linkage stud- this particular mutation in the GUCY2D gene. ies, it is important to account for this in the model (para-

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©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 metric analysis) of the disease as an age-dependant Funding/Support: This study was funded in part by a grant penetrance that is not complete (ie, incomplete pen- from the Foundation Fighting Blindness. etrance). This seems to be an important feature of GUCY2D mutations. REFERENCES Five different mutations (E837D, R838C, R838H, G838S, and T839M in exon 13) in the GUCY2D gene caus- 1. Krill AE. Cone degenerations. In: Krill AE, Archer DB, eds. Hereditary Retinal and ing cone-rod degeneration have been described previ- Choroidal Diseases. Vol 2. Hagerstown, MD: Harper & Row; 1977:421-478. ously.41-54 The functional consequences of these guanyl- 2. Berson EL, Gouras P, Gunkel RD. Progressive cone degeneration, dominantly ate cyclase mutations leading to cone-rod degeneration inherited. 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From the Archives of the Archives

We avoided making the section through the trephine bleb because of possible interference with its function, and because in several cases prior to this series unfortunate end results had followed section through the bleb. We did not make the section in the clear cornea anterior to the bleb because of the difficulty of removing a lens in its capsule from under an overhanging shelf and the fear of corneal scarring in the pupillary area. Reference: Callahan A. Cataract extraction after glaucoma surgery: lateroinferior approach following filter- ing glaucoma operation. Arch Ophthalmol. 1952;47:133.

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