|Molecular Vision 2005;
Received 29 November 2004 | Accepted 18 January 2005 | Published 20 February 2005
Autosomal dominant cone dystrophy caused by a novel mutation in the GCAP1 gene (GUCA1A)
Li Jiang,1,2,3 Bradley
J. Katz,1,2 Zhenglin Yang,1,2,4 Yu Zhao,1,2 Nathan
Faulkner,1,2 Jianbin Hu,1,2,4 Jennifer Baird,1
Wolfgang Baehr,1,3,5 Donnell J.
Creel,1 Kang Zhang1,2,5
Departments of 1Ophthalmology and Visual Sciences, 3Biology, and 5Neurobiology and Anatomy, and the 2Program in Human Molecular Biology and Genetics, University of Utah Health Sciences Center, Salt Lake City, UT; 4Sichuan Provincial Medical Academy & Sichuan Provincial People's Hospital, Sichuan, People's Republic of China
Correspondence to: Dr. Kang Zhang, Eccles Institute of Human Genetics, 15 North 2030 East, Building 533, Room 3060A, University of Utah Health Science Center, Salt Lake City, UT, 84132; Phone: (801) 585-6797; FAX: (801) 585-3501; email: firstname.lastname@example.org
Purpose: To describe the clinical features and genetic analysis of a family with an autosomal dominant cone dystrophy (adCD).
Methods: Selected members of a family with an autosomal dominant cone dystrophy underwent ophthalmic evaluation. Blood samples were obtained, genomic DNA was isolated, and genomic fragments were amplified by PCR. Linkage to locus D6S1017 was established. DHPLC mutational analysis and direct sequencing were used to identify a mutation in GUCA1A, the gene encoding the guanylate cyclase activating protein 1 (GCAP1).
Results: Of 24 individuals who are at risk of the disease in a five generation family, 11 members were affected. Clinical presentations included photophobia, color vision defects, central acuity loss, and legal blindness with advanced age. The disease phenotype was observed in the second and third decades of life and segregated in an autosomal dominant fashion. An electroretinogram performed on one proband revealed profoundly subnormal and prolonged photopic and flicker responses, but preserved scotopic ERGs, consistent with a cone dystrophy. Mutational analysis and direct sequencing revealed a C451T transition in GUCA1A, corresponding to a novel L151F mutation in GCAP1. Like the E155G mutation, this mutation occurs in the EF4 hand domain, a region of GCAP1 critical in conferring calcium sensitivity to the protein. The leucine at this position is highly conserved among vertebrate guanylate cyclase activating proteins.
Conclusions: A novel L151F missense mutation in the EF4 high affinity Ca2+ binding site of GCAP1 is linked to adCD in a large pedigree. The cone dystrophy in this family shares clinical and electrophysiologic characteristics with other previously described adCD caused by mutations in GUCA1A.
The cone dystrophies are a phenotypically heterogeneous group of hereditary retinal degenerations characterized by progressive dysfunction of the photopic (cone mediated) system, presenting with hemeralopia (day blindness), loss of color vision, reduced central visual acuity, and preserved peripheral vision . Cone dystrophies may be contrasted to rod dystrophies, such as retinitis pigmentosa, which are characterized by abnormalities in scotopic (rod mediated) functions, manifesting as night blindness, preserved central visual acuity early in the disease process, and constricted peripheral vision. Early in the disease process, the fundus appearance of a patient with a cone dystrophy may be normal. The disease is then diagnosed based on characteristic changes in the electroretinogram. Later in the disease process, the retinal pigment epithelium may take on a granular appearance that may progress to central atrophy.
Like retinis pigmentosa (RP), the cone dystrophies are genetically heterogeneous and may present as a sporadic, autosomal dominant, autosomal recessive, or X-linked recessive trait (RetNet). Identified genes linked to autosomal dominant cone dystrophies include GUCY2D, encoding photoreceptor guanylate cyclase 1 (retGC-1, or GC1) and GUCA1A, encoding the photoreceptor specific Ca2+ binding protein termed guanylate cyclase activating protein 1 (GCAP1). GC1 and GCAP1 are key components in the phototransduction cascade in rod and cone photoreceptors. In the dark adapted state, photoreceptors have high levels of cGMP and this molecule holds photoreceptor plasma membrane cation channels open. Exposure to light initiates the phototransduction cascade in photoreceptors, resulting in the hydrolysis of cGMP and closure of the cGMP-gated cation channels [2-4]. The concentration of free intracellular Ca2+ decreases as a consequence of continued activity of the Na+/Ca2+-K+ exchanger (NCKX) exchanger also located in the plasma membrane, an event that in turn activates guanylate cyclases . The stimulation of the guanylate cyclases by decreased levels of calcium occurs indirectly via GCAPs [5-7]. The GCAP-stimulated GC activity eventually returns cGMP to levels that are sufficient to re-open the cGMP-gated cation channels, establishing the dark adapted state.
The GCAPs are neuron specific calcium binding proteins (NCBPs), a subgroup of the large calmodulin supergene family with four EF hand  motifs . NCBPs include recoverins, another set of photoreceptor specific Ca2+ binding proteins, frequenins, hippocalcins and hippocalcin-like proteins, neuronal Ca2+ sensors and many others . Unlike calmodulin and other NCBPs, the GCAPs activate their target proteins, the guanylate cyclases, when the concentration of free intracellular Ca2+ is low , while other NCBPs activate their targets when the concentration of free Ca2+ is high. Up to eight GCAPs have been identified in vertebrates , but in human retina there are only three (GCAP1, GCAP2, and GCAP3). The mouse appears to express only GCAP1 and GCAP2, but not GCAP3 [11,13]. The human and mouse GCAP1 and GCAP2 genes reside in a tail-to-tail array on chromosome 6p21.1 and chromosome 17, respectively, and share a four-exon/three-intron arrangement [14,15]. GCAP3 has the same exon/intron arrangement, but has been localized to 3q13.1 . Thus, it appears that these three GCAP genes arose as a result of the duplication and translocation of a common ancestral gene.
Four different mutations linked to retina disease have been previously described in GCAP1 (Y99C, P50L, E155G, and I143NT) [16-20]. All are missense mutations, one (I143NT) has an insertion of an additional amino acid residue. Loss of Ca2+ sensitivity is associated with the Y99C, E155G, and I143NT mutations. Common to these is that the mutation affects one of the three functional EF hand motifs in GCAP1 (EF3 or EF4). The biochemical effect of the mutations consists of the inability of the mutant GCAPs to inhibit photoreceptor GC in the dark, when Ca2+ is elevated [21,22]. The result is that cGMP levels are elevated in mutant photoreceptors, and a larger number of cation channels remain open, which eventually leads to elevated Ca2+ concentration and to photoreceptor cell death . In this manuscript, we describe the clinical features of and the genetic mutations in a family with an autosomal dominant cone dystrophy carrying a novel missense mutation in the GUCA1 gene.
This study was approved by the Institutional Review Board of the University of Utah Hospitals and Clinics and all subjects provided informed consent prior to participation. Some subjects underwent complete ophthalmologic examination including visually acuity measurements and fundus examinations. Other subjects were interviewed by telephone. Blood samples were obtained by venipuncture. Patients were diagnosed with cone dystrophy if they showed the classic triad of photophobia, decreased color vision, and decreased visual acuity.
One patient underwent electroretinography. Electroretinograms (ERGs) were recorded using standard electrophysiologic methods (D. Creel, Clinical Electrophysiology, Webvision). The subject was dark adapted for 30 min. Reference and ground electrodes were each attached to an earlobe. Using an indirect headlamp with several Wratten 26 red filters simulating a mobile dark room "safe" light, a Burian-Lawwill speculum contact lenses was inserted to record ERGs from the cornea. Responses were obtained using a Nicolet ganzfeld bowl, amplifier, and computer. Responses were differentially amplified (band pass 0.1-1000 Hz), averaged, and stored. Amplitude band pass sensitivity was one millivolt. ERGs were recorded using single scotopically balanced dim blue and red flashes, and bright white flashes. Patients were then light adapted with background illumination of 3.18x104 cd/m2 for 10 min and photopic ERGs were recorded using 30 Hz flicker following and the same bright white flash.
Genetic linkage and mutation screening
Genomic DNA was extracted from blood samples using a Qiagen DNA isolation kit according to the manufacturer's specifications (QIAGEN, Valencia, CA). Linkage to microsatellite marker D6S1017, linked to the GCAP1 locus was assessed using established methods . Each of the four exons of GCAP1 were then amplified by PCR using flanking intron specific primers (Table 1) and screened for mutations by denaturing high performance liquid chromatography (DHPLC; WAVE® System, Transgenomic, Omaha, NE). Sequence alterations were identified by direct sequencing with a CEQ Dye Terminator Cycle Sequencing Kit on Beckman-Coulter CEQ 8000 Genetic Analysis System, according to the manufacturer's instructions and using established methods [25,26].
Fundus photographs and fluorescein angiography were performed using a TOPCON digital fundus camera according to the manufacturer's specification (TOPCON America Corporation, Pleasanton, CA).
The alignments of FastA versions of GCAP amino acid sequences were generated by Clustal W (version 1.82). The GenBank accession numbers for the amino acid sequences are in Table 2.
Clinical evaluation of the family with adCORD
The pedigree consisted of 30 living members of a five generation family (Figure 1A) in which the disease was inherited in an autosomal dominant pattern. Clinical characteristics of the family (Table 3) included photophobia, color vision defects and central acuity loss. Most subjects within the family noted symptoms in the second and third decades of life. Visual acuity ranged from younger individuals with normal or nearly normal visual function to older individuals with legal blindness. Representative fundus photos from two individuals from this pedigree are presented in Figure 2. The proband IV:1 at age 36 is mildly affected. Fundus examinations revealed only subtle pigmentary changes in the macula (Figure 2A,B). However, the fundus fluorescent angiogram of this individual (Figure 2C,D) revealed more marked atrophic changes in the macula than can be seen on fundus examination. The mother of the proband at age 64 is more severely affected and has geographic atrophy of the retina and retinal pigment epithelium (Figure 2E,F).
The dim blue scotopic ERG response (mostly rod response) of the proband is essentially normal. The dim red scotopic ERG predominantly reflects rod activity, but also reflects some cone activity. Thus the normal subject's dim red ERG has an a-wave, an early, small b-wave labeled bx, and oscillatory potentials on the ascending limb of the b-wave. The early a-wave, bx-wave, and oscillatory potentials reflect cone activity, and these responses are absent in the proband's ERG. The scotopic bright white ERG is minimally abnormal with an attenuated b-wave amplitude and slow implicit time. The 30 Hz flicker response and the photopic white ERG were profoundly subnormal and prolonged. Electrophysiologically, the manifestations of the L151F phenotype closely resemble that of the Y99C, E155G, and I143NT mutations where photopic responses and flickers were non-recordable [16,19,20]. Rod responses and maximal dark adapted single white flash responses were only mildly subnormal in amplitude.
An initial genotype analysis with marker D6S1017 yielded a LOD score of 3.3 at θ=0.00, consistent with linkage to GUCA1A. Subsequently, DHPLC mutation screening and direct sequencing identified a C451T transition resulting in a novel L151F change in the GCAP1 amino acid sequences in all affected individuals (Figure 1C). This mutation segregated with the disease phenotype and was not found in 200 normal controls. Like the E155G  and the I143NT  mutation, the L151F mutation occurs within the fourth EF-hand domain of GCAP1.
Progressive cone dystrophies are inherited in an autosomal recessive, autosomal dominant, or X-linked fashion, and are caused by a heterogeneous set of genes (Table 4) . These genes include phototransduction genes like GNAT2, which encodes the cone transducin α subunit, the CNGA3 and CNGB3 genes, which encode subunits of the cGMP-gated cation channel, and the genes GUC2D and GUC1A, which encode GC1 and GCAP1. Also contained in this group are transcription factors (CRX), genes involved in the retinoid cycle (ABCA4, RDH5), and genes involved in protein transport through the cilium (RPGR and RPGRIP). A number of loci are known for which the corresponding gene has yet to be identified (RetNet).
We have described the clinical features of twelve subjects in a five generation family with an autosomal dominant cone dystrophy (Table 3). This disease was found to be caused by a novel mutation in GUCA1A affecting the EF4 high affinity Ca2+ binding site of GCAP1. The phenotype of affected family members carrying the L151F mutation is clinically very similar to three of the four previously described mutations in GUCA1A. Initial symptoms of reduced central acuity and loss of color vision became apparent in the second and third decades. It appears that all affected individuals eventually progress to legal blindness, with visual acuities between 20/200 and 20/400. Funduscopic changes were initially subtle, but progressed to central atrophy over time. The L151F phenotype resembles the Y99C mutation in severity, but the age of onset of clinical symptoms is somewhat earlier in patients with the L151F mutation.
EF hands represent high affinity Ca2+ binding sites and are responsible for the calcium sensitivity of the GCAP/GC system. Not surprisingly, mutations within these domains were shown to alter calcium sensitivity [16,21,22]. Some of the amino acids within the domain contain oxygen in their side chains that facilitate calcium coordination [27,28]. Although the L151 residue does not directly participate in calcium binding, the L151F mutation affects the structure of the EF-hand domain and thereby affects calcium sensitivity . Review of the sequences of 30 GCAPs in 8 vertebrate species (Figure 3) revealed that the L151 residue is highly conserved. Only the more distantly related GCAP6-8 of pufferfish and the guanylate cyclase-inhibitory proteins (GCIPs) carry a chemically similar isoleucine at this position. The presence of isoleucine is not considered to interfere with Ca2+ binding to EF4 since it conforms with the EF hand consensus sequence . Replacement of L151 by phenylalanine is also considered a conservative substitution since both Leu and Phe are hydrophobic and not much different in size . However, even conservative substitutions can alter binding of Ca2+ to EF hand loops significantly. For example, An E155D mutant of GCAP1 (replacement of an acidic Glu by another acidic residue, Asp), drastically reduced Ca2+ sensitivity of E155D-GCAP1 .
We conclude that the L151F mutation is pathogenic for the following reasons. First, the mutation segregates with disease in a large five generation pedigree with 30 family members. Second, this mutation was not found in over 200 controls. Third, the mutation affects the high affinity Ca2+ binding site EF4, which has been shown to be key for Ca2+ sensitivity of GCAP1 in vitro [31,32]. Fourth, two other mutations in EF4 have been linked to dominant cone dystrophy [16,20]. Fifth, the L151F mutations was found to be pathogenic in an autosomal dominant cone/rod dystrophy in an unrelated pedigree .
Supported by NIH K23 RR16427 (BJK), NIH R01 EY14428 (KZ), NIH R01 EY14448 (KZ), EY08123 (WB); RCL Foundation (KZ), the American Health Assistance Foundation (KZ); the Karl Kirchgessner Foundation (KZ); the Ruth and Milton Steinbach Fund (KZ); Ronald McDonald House Charities (KZ); The Macular Vision Research Foundation, Val and Edith Green Foundation (KZ); an unrestricted grant to the Department of Ophthalmology and Visual Sciences from Research to Prevent Blindness, Inc., New York, NY, and a Center Grant from the Foundation Fighting Blindness, Inc.
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