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

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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 Ctive 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. (REPRINTED) ARCH OPHTHALMOL / VOL 126 (NO. 3), MAR 2008 WWW.ARCHOPHTHALMOL.COM 397 ©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 re- gion. New polymorphic markers were identified by analyzing sequences from clones (GenBank AD005695). Flanking prim- ers 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 devel- oped 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 re- gion. 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 electrooculogra- phy 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
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