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• W1991804865 abstract "SummaryStargardt disease (STGD) is the most common hereditary macular dystrophy and is characterized by decreased central vision, atrophy of the macula and underlying retinal-pigment epithelium, and frequent presence of prominent flecks in the posterior pole of the retina. STGD is most commonly inherited as an autosomal recessive trait, but many families have been described in which features of the disease are transmitted in an autosomal dominant manner. A recessive locus has been identified on chromosome 1p (STGD1), and dominant loci have been mapped to both chromosome 13q (STGD2) and chromosome 6q (STGD3). In this study, we describe a kindred with an autosomal dominant Stargardt-like phenotype. A genomewide search demonstrated linkage to a locus on chromosome 4p, with a maximum LOD score of 5.12 at a recombination fraction of .00, for marker D4S403. Analysis of extended haplotypes localized the disease gene to an ∼12-cM interval between loci D4S1582 and D4S2397. Therefore, this kindred establishes a new dominant Stargardt-like locus, STGD4. Stargardt disease (STGD) is the most common hereditary macular dystrophy and is characterized by decreased central vision, atrophy of the macula and underlying retinal-pigment epithelium, and frequent presence of prominent flecks in the posterior pole of the retina. STGD is most commonly inherited as an autosomal recessive trait, but many families have been described in which features of the disease are transmitted in an autosomal dominant manner. A recessive locus has been identified on chromosome 1p (STGD1), and dominant loci have been mapped to both chromosome 13q (STGD2) and chromosome 6q (STGD3). In this study, we describe a kindred with an autosomal dominant Stargardt-like phenotype. A genomewide search demonstrated linkage to a locus on chromosome 4p, with a maximum LOD score of 5.12 at a recombination fraction of .00, for marker D4S403. Analysis of extended haplotypes localized the disease gene to an ∼12-cM interval between loci D4S1582 and D4S2397. Therefore, this kindred establishes a new dominant Stargardt-like locus, STGD4. Age-related macular degeneration (AMD) represents a heterogeneous group of retinal disorders and is the most common cause of irreversible blindness among elderly individuals in the United States (Bressler et al. Bressler et al., 1988Bressler NM Bressler SB Fine SL Age-related macular degeneration.Surv Ophthalmol. 1988; 32: 375-413Abstract Full Text PDF PubMed Scopus (743) Google Scholar). Stargardt disease (STGD) shows some similarities to AMD. It is the most common hereditary macular dystrophy, with a prevalence of ∼1/10,000. Clinically, STGD is characterized by decreased central vision during the first several decades of life, bilateral “bull's-eye” atrophy or a “beaten-bronze” appearance of the macula and underlying retinal-pigment epithelium, and frequent presence of prominent yellow “flavimaculatus flecks” in the posterior pole of the retina (Stargardt Stargardt, 1909Stargardt K Über familiäre progressive Degeneration in der Makulagegend des Auges.Albrecht Graefes Arch Klin Exp Ophthalmol. 1909; 71: 534-549Crossref Scopus (264) Google Scholar; Hadden and Gass Hadden and Gass, 1976Hadden OB Gass JDM Fundus flavimaculatus and Stargardt's disease.Am J Ophthalmol. 1976; 82: 527-539Abstract Full Text PDF PubMed Scopus (93) Google Scholar; Noble and Carr Noble and Carr, 1979Noble KG Carr RE Stargardt's disease and fundus flavimaculatus.Arch Ophthalmol. 1979; 97: 1281-1285Crossref PubMed Scopus (128) Google Scholar). Fluorescein angiography reveals a virtually pathognomonic “dark choroid” pattern (Fish et al. Fish et al., 1981Fish G Grey R Sehmi KS Bird AC The dark choroid in posterior retinal dystrophies.Br J Ophthalmol. 1981; 65: 359-363Crossref PubMed Scopus (70) Google Scholar). Electroretinography is normal early in the course of the disease but often shows mild to moderate abnormalities in late stages (Fishman Fishman, 1976Fishman GA Fundus flavimaculatus: a clinical classification.Arch Ophthalmol. 1976; 94: 2061-2067Crossref PubMed Scopus (147) Google Scholar). Classically, STGD is inherited in an autosomal recessive manner. A recessive locus has been mapped to chromosome 1p (STGD1 [MIM 248200]), and the corresponding gene on chromosome 1p has been cloned (Kaplan et al. Kaplan et al., 1993Kaplan J Gerber S Larget-Piet D Rozet JM Dollfus H Dufier JL Odent S et al.A gene for Stargardt's disease (fundus flavimaculatus) maps to the short arm of chromosome 1.Nat Genet. 1993; 5: 308-311Crossref PubMed Scopus (148) Google Scholar; Allikmets et al. Allikmets et al., 1997bAllikmets R Singh N Sun H Shroyer NF Hutchinson A Chidambaram A Gerrard B et al.A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy.Nat Genet. 1997b; 15: 236-246Crossref PubMed Scopus (1023) Google Scholar). This gene encodes a retina-specific transmembrane protein, ABCR, which belongs to the ATP-binding cassette family of membrane transporters. It is of particular interest that mutations in the ABCR gene have been reported in a subset of patients with AMD (Allikmets et al. Allikmets et al., 1997aAllikmets R Shroyer NF Singh N Seddon JM Lewis RA Bernstein PS Peiffer A et al.Mutation of the Stargardt disease gene (ABCR) in age-related macular degeneration.Science. 1997a; 277: 1805-1807Crossref PubMed Scopus (721) Google Scholar), although it should be noted that the interpretation of this finding is controversial (Dryja et al. Dryja et al., 1998Dryja TP Briggs CE Berson EL Rosenfeld PJ Abitbol M ABCR gene and age-related macular degeneration.Science. 1998; 279: 1107(http://www.sciencemag.org/cgi/content/full/279/5354/1107a)Crossref Google Scholar; Klaver et al. Klaver et al., 1998Klaver CCW Assink JJM Bergen AAB van Duijin CM ABCR and age-related macular degeneration.Science. 1998; 279: 1107(http://www.sciencemag.org/cgi/content/full/279/5354/1107a)Crossref Google Scholar; Stone et al. Stone et al., 1998Stone EM Webster AR Vandenburgh K Streb LM Hockey RR Lotery AJ Sheffield VC Allelic variation in ABCR associated with Stargardt disease but not age-related macular degeneration.Nat Genet. 1998; 20: 328-329Crossref PubMed Scopus (174) Google Scholar). In addition to the more common recessive pattern, many families have been described in which features of STGD are transmitted in an autosomal dominant manner (Cibis et al. Cibis et al., 1980Cibis GW Morey M Harris DJ Dominantly inherited macular dystrophy with flecks (Stargardt).Arch Ophthalmol. 1980; 98: 1785-1789Crossref PubMed Scopus (52) Google Scholar; Lopez et al. Lopez et al., 1990Lopez PF Maumenee IH Cruz Z Green WR Autosomal-dominant fundus flavimaculatus: clinicopathologic correlation.Ophthalmology. 1990; 97: 798-809Abstract Full Text PDF PubMed Scopus (93) Google Scholar; Mansour Mansour, 1992Mansour AM Long-term follow-up of dominant macular dystrophy with flecks (Stargardt).Ophthalmologica. 1992; 205: 138-143Crossref PubMed Scopus (24) Google Scholar; Stone et al. Stone et al., 1994Stone EM Nichols BE Kimura AE Weingeist TA Drack A Sheffield VC Clinical features of a Stargardt-like dominant progressive macular dystrophy with genetic linkage to chromosome 6q.Arch Ophthalmol. 1994; 112: 765-772Crossref PubMed Scopus (140) Google Scholar; Zhang et al. Zhang et al., 1994Zhang K Bither PP Park R Donoso LA Siedman JG Siedman CE A dominant Stargardt's macular dystrophy maps to chromosome 13q34.Arch Ophthalmol. 1994; 112: 759-764Crossref PubMed Scopus (74) Google Scholar). Dominant loci have been mapped to chromosome 13q (STGD2 [MIM 153900]) and to chromosome 6q (STGD3 [MIM 600110]) (Stone et al. Stone et al., 1994Stone EM Nichols BE Kimura AE Weingeist TA Drack A Sheffield VC Clinical features of a Stargardt-like dominant progressive macular dystrophy with genetic linkage to chromosome 6q.Arch Ophthalmol. 1994; 112: 765-772Crossref PubMed Scopus (140) Google Scholar; Zhang et al. Zhang et al., 1994Zhang K Bither PP Park R Donoso LA Siedman JG Siedman CE A dominant Stargardt's macular dystrophy maps to chromosome 13q34.Arch Ophthalmol. 1994; 112: 759-764Crossref PubMed Scopus (74) Google Scholar). In this report, we describe a kindred affected with an autosomal dominant form of STGD mapping to a new disease locus, on chromosome 4. In accordance with the guidelines of the HUGO Nomenclature Committee, the gene causing this disorder has been designated “STGD4.” Linkage was established with a two-point maximum LOD score (Zmax) of 5.12 at θ=.00, between the disease and marker locus D4S403, and a 10-cM critical region between marker loci D4S1582 and D4S2397 was identified by analysis of extended haplotypes. Informed consent was obtained from all participants, in accordance with the guidelines established by the Johns Hopkins University School of Medicine, Baltimore. Twenty-six members of a three-generation, nonconsanguineous Caribbean family were identified for study. A complete ophthalmic history was obtained, and an examination was performed on each subject. Individuals were considered to be affected on the basis of the presence of decreased visual acuity and bull's-eye or similar macular atrophy. Fluorescein angiography was done in four affected subjects, and two affected subjects underwent electroretinographic testing. Blood was collected from family members by venipuncture, and genomic DNA was isolated with the QIAamp™ blood kit (Qiagen), according to the manufacturer's instructions. All DNA samples were analyzed with polymorphic short tandem repeat (STR) markers spanning 22 autosomes, with a step of ∼24.2 cM (Research Genetics). PCR was performed according to the manufacturer's protocol (Research Genetics). In most cases, multiplex PCR was used. After amplification, PCR fragments were separated on a denaturing 6% polyacrylamide gel, and bands were visualized by exposure of the dry gel to x-ray film (Kodak). Two-point and multipoint linkage analysis was conducted with the LINKAGE (version 5.1) package (Lathrop et al. Lathrop et al., 1985Lathrop GM Lalouel JM Julier C Ott J Multilocus linkage analysis in humans: detection of linkage and estimation of recombination.Am J Hum Genet. 1985; 37: 482-498PubMed Google Scholar). Linkage analysis was done under conditions of no sex differences in recombination, complete disease penetrance, and disease-gene frequency of 1/10,000. Allele frequencies for the markers used were determined by the genotyping of 40 additional chromosomes. The reference genetic map used for linkage analysis was obtained from the Human Gene Map (Dib et al. Dib et al., 1996Dib C Faure S Fizames C Samson D Drouot N Vignal A Millasseau P et al.A comprehensive genetic map of the human genome based on 5,264 microsatellites.Nature. 1996; 380: 152-154Crossref PubMed Scopus (2668) Google Scholar). Extended haplotypes of the individuals were constructed according to the order of STR markers in the Généthon genetic linkage map (Dib et al. Dib et al., 1996Dib C Faure S Fizames C Samson D Drouot N Vignal A Millasseau P et al.A comprehensive genetic map of the human genome based on 5,264 microsatellites.Nature. 1996; 380: 152-154Crossref PubMed Scopus (2668) Google Scholar). Reconstruction of haplotypes was done, whenever possible, for individuals whose DNA samples were not available. Twelve of the 18 individuals at risk for inheriting the disease were found to be affected, on the basis of the presence of decreased visual acuity and macular atrophy (fig. 1A). Fluorescein angiography was done in four affected subjects, all of whom demonstrated the characteristic dark-choroid pattern of STGD. Three of the four fluorescein angiograms revealed typical STGD flavimaculatus flecks (fig. 1B). In addition, two affected subjects underwent electroretinographic testing. One of these individuals had a normal rod-photoreceptor response and a mildly decreased cone-photoreceptor response, and the other had a very mildly reduced rod response and a mildly reduced cone response (authors' unpublished data). A pedigree was constructed, with affected members of both sexes in each generation (fig. 2). Taken together, these data are consistent with autosomal dominant transmission of a Stargardt-like disease.Figure 2Autosomal dominant Stargardt-like–disease pedigree. Boxes indicate the disease haplotypes. Squares denote males; circles denote females; blackened symbols denote affected individuals; unblackened symbols denote unaffected individuals; a diagonal slash through a symbol denotes that the individual is deceased; dashes (−) denote that data were not available.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Polymorphic STR markers previously known to be linked to STGD, cone dystrophy (COD), and cone-rod dystrophy (CORD) were examined first. The analyzed loci included STGD2 on 13q34 (Zhang et al. Zhang et al., 1994Zhang K Bither PP Park R Donoso LA Siedman JG Siedman CE A dominant Stargardt's macular dystrophy maps to chromosome 13q34.Arch Ophthalmol. 1994; 112: 759-764Crossref PubMed Scopus (74) Google Scholar), STGD3 on 6q (Stone et al. Stone et al., 1994Stone EM Nichols BE Kimura AE Weingeist TA Drack A Sheffield VC Clinical features of a Stargardt-like dominant progressive macular dystrophy with genetic linkage to chromosome 6q.Arch Ophthalmol. 1994; 112: 765-772Crossref PubMed Scopus (140) Google Scholar), COD3 (MIM 602093) on 6p21 (Payne et al. Payne et al., 1998Payne AM Downes SM Bessant DA Taylor R Holder GE Warren MJ Bird AC et al.A mutation in guanylate cyclase activator 1A (GUCA1A) in an autosomal dominant cone dystrophy pedigree mapping to a new locus on chromosome 6p21.1.Hum Mol Genet. 1998; 7: 273-277Crossref PubMed Scopus (192) Google Scholar), CORD2 (MIM 120970) on 19q13 (Evans et al. Evans et al., 1994Evans K Fryer A Inglehearn C Duvall-Young J Whittaker JL Gregory CY Butler R et al.Genetic linkage of cone-rod retinal dystrophy to chromosome 19q and evidence for segregation distortion.Nat Genet. 1994; 6: 210-213Crossref PubMed Scopus (90) Google Scholar; Freund et al. Freund et al., 1997Freund CL Gregory-Evans CY Furukawa T Papaioannou M Looser J Ploder L Bellingham J et al.Cone-rod dystrophy due to mutations in a novel photoreceptor-specific homeobox gene (CRX) essential for maintenance of the photoreceptor.Cell. 1997; 91: 543-553Abstract Full Text Full Text PDF PubMed Scopus (434) Google Scholar; Swain et al. Swain et al., 1997Swain PK Chen S Wang QL Affatigato LM Coats CL Brady KD Fishman GA et al.Mutations in the cone-rod homeobox gene are associated with the cone-rod dystrophy photoreceptor degeneration.Neuron. 1997; 19: 1329-1336Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar), CORD5 (MIM 600977) on 17p (Small et al. Small et al., 1996Small KW Syrquin M Mullen L Gehrs K Mapping of autosomal dominant cone degeneration to chromosome 17p.Am J Ophthalmol. 1996; 121: 13-18Abstract Full Text PDF PubMed Scopus (35) Google Scholar), and CORD6 (MIM 601777) on chromosome 17p12-p13 (Kelsell et al. Kelsell et al., 1997Kelsell RE Evans K Gregory CY Moore AT Bird AC Hunt DM Localisation of a gene for dominant cone-rod dystrophy (CORD6) to chromosome 17p.Hum Mol Genet. 1997; 6: 597-600Crossref PubMed Scopus (45) Google Scholar). No significant linkage was found to any of these loci. A genomewide scan with 147 STR markers was performed, and linkage was found after 59% of the genome was excluded as a location of the disease gene. Two-point linkage analysis revealed a locus on chromosome 4, with Zmax=5.12 at θ=.00, for marker D4S403 (table 1). Linkage analysis was refined with 14 additional STR markers spanning a 32-cM region centered around marker D4S403. The LOD scores for loci D4S2639, D4S1602, and D4S1601 also satisfied the Morton (Morton, 1955Morton NE Sequential tests for the detection of linkage.Am J Hum Genet. 1955; 7: 277-318PubMed Google Scholar) criterion, reaching Zmax>4.0 at θ=.00. Multipoint linkage analysis (fig. 3) localized the disease interval to a region between markers D4S1582 and D4S2397, with 3-unit-LOD-score support interval ∼10–22 cM to the right of marker D4S3007.Table 1Two-Point LOD Scores between Dominant Stargardt-Like Disease and DNA MarkersLOD Score at θ =Marker.00.01.06.11.16.21.26.31.36.41D4S3007−∞-2.12.09.69.941.031.01.91.75.53D4S1582−∞-.131.281.601.661.601.461.261.00.69D4S26394.214.153.813.453.082.682.261.811.35.87D4S2944.55.51.50.46.43.38.32.26.19.12D4S16024.824.744.363.963.533.082.602.091.561.012D4S4035.125.044.634.203.763.282.772.231.671.08D4S16014.824.744.363.963.533.082.602.091.561.01D4S2397−∞.161.421.641.651.561.391.18.93.63 Open table in a new tab Extended haplotypes were constructed on the basis of the following order of markers: D4S3007–D4S1582–D4S2639–D4S2944–D4S1602–D4S403–D4S1601–D4S2397 (fig. 2). These loci represent a region 12–32 cM from the top of the chromosome. The presumptive disease-associated haplotype was determined as a common extended haplotype for all affected individuals. Eight informative recombination events were identified in the family. On the basis of these results, the disease interval was localized between markers D4S1582 and D4S2397 on chromosome 4p. Within the region, no recombinations were detected at loci D4S2639, D4S2944, D4S1602, D4S403, and D4S1601. STGD was originally described as an autosomal recessive trait (Stargardt Stargardt, 1909Stargardt K Über familiäre progressive Degeneration in der Makulagegend des Auges.Albrecht Graefes Arch Klin Exp Ophthalmol. 1909; 71: 534-549Crossref Scopus (264) Google Scholar). STGD1, a chromosome 1p gene responsible for autosomal recessive STGD, has recently been cloned (Allikmets et al. Allikmets et al., 1997bAllikmets R Singh N Sun H Shroyer NF Hutchinson A Chidambaram A Gerrard B et al.A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy.Nat Genet. 1997b; 15: 236-246Crossref PubMed Scopus (1023) Google Scholar). Autosomal dominant inheritance of a Stargardt-like phenotype is less common but has been described in a number of families (Cibis et al. Cibis et al., 1980Cibis GW Morey M Harris DJ Dominantly inherited macular dystrophy with flecks (Stargardt).Arch Ophthalmol. 1980; 98: 1785-1789Crossref PubMed Scopus (52) Google Scholar; Lopez et al. Lopez et al., 1990Lopez PF Maumenee IH Cruz Z Green WR Autosomal-dominant fundus flavimaculatus: clinicopathologic correlation.Ophthalmology. 1990; 97: 798-809Abstract Full Text PDF PubMed Scopus (93) Google Scholar; Mansour Mansour, 1992Mansour AM Long-term follow-up of dominant macular dystrophy with flecks (Stargardt).Ophthalmologica. 1992; 205: 138-143Crossref PubMed Scopus (24) Google Scholar; Stone et al. Stone et al., 1994Stone EM Nichols BE Kimura AE Weingeist TA Drack A Sheffield VC Clinical features of a Stargardt-like dominant progressive macular dystrophy with genetic linkage to chromosome 6q.Arch Ophthalmol. 1994; 112: 765-772Crossref PubMed Scopus (140) Google Scholar; Zhang et al. Zhang et al., 1994Zhang K Bither PP Park R Donoso LA Siedman JG Siedman CE A dominant Stargardt's macular dystrophy maps to chromosome 13q34.Arch Ophthalmol. 1994; 112: 759-764Crossref PubMed Scopus (74) Google Scholar). Previous studies have identified two loci for dominant Stargardt-like disease: STGD2 and STGD3 (Stone et al. Stone et al., 1994Stone EM Nichols BE Kimura AE Weingeist TA Drack A Sheffield VC Clinical features of a Stargardt-like dominant progressive macular dystrophy with genetic linkage to chromosome 6q.Arch Ophthalmol. 1994; 112: 765-772Crossref PubMed Scopus (140) Google Scholar; Zhang et al. Zhang et al., 1994Zhang K Bither PP Park R Donoso LA Siedman JG Siedman CE A dominant Stargardt's macular dystrophy maps to chromosome 13q34.Arch Ophthalmol. 1994; 112: 759-764Crossref PubMed Scopus (74) Google Scholar). In the present study, we have performed genetic-linkage analysis of a kindred affected with autosomal dominant Stargardt-like disease. A genomewide search identified a chromosome 4 region containing the disease gene, with several STR markers cosegregating with the disease phenotype. A two-point Zmax of 5.12 at θ=.00 was obtained between the disease and marker locus D4S403. Multipoint analysis and analysis of extended haplotypes disclosed recombination events that restricted the disease interval to an ∼12-cM region between markers D4S1582 and D4S2397. This defines a new locus, STGD4, for autosomal dominant Stargardt-like disease. A candidate-gene search of a gene map of the human genome (Deloukas et al. Deloukas et al., 1998Deloukas P Schuler GD Gyapay G Beasley EM Soderlund C Rodriguez-Tome P Hui L et al.A physical map of 30,000 human genes.Science. 1998; 282: 744-746Crossref PubMed Scopus (576) Google Scholar) identified two genes in this region that are expressed in the retina. The first gene encodes dihydropyrimidinase-related protein-1 (DRP-1) and has been mapped by Généthon by means of the radiation-hybrid panel. The biological function of DRP-1 is unknown, but two homologous proteins, DRP-2 and DRP-3, are thought to play a role in neuronal growth and maturation (Hamajima et al. Hamajima et al., 1996Hamajima N Matsuda K Sakata S Tamaki N Sasaki M Nonaka M A novel gene family defined by human dihydropyrimidinase and three related proteins with differential tissue distribution.Gene. 1996; 180: 157-163Crossref PubMed Scopus (198) Google Scholar). The second gene encodes heat-shock protein 90 (HSP90 [MIM 140572]). It has been mapped by the Whitehead Institute for Biomedical Research/MIT Center for Genome Research by means of a YAC panel and belongs to a family of stress-inducible proteins (Rebbe et al. Rebbe et al., 1989Rebbe NF Hickman WS Ley TJ Stafford DW Hickman S Nucleotide sequence and regulation of a human 90-kDa heat shock protein gene.J Biol Chem. 1989; 264: 15006-15011Abstract Full Text PDF PubMed Google Scholar). Heat-shock proteins are associated with various cellular signaling proteins and are believed to maintain tissue integrity against thermal, oxidative, and mechanical stresses. In particular, HSP90 has been shown to be expressed in rodents during visual-system development (Kojima et al. Kojima et al., 1996Kojima M Hoshimaru M Aoki T Takahashi JB Ohtsuka T Asahi M Matsuura N et al.Expression of heat shock proteins in the developing rat retina.Neurosci Lett. 1996; 205: 215-217Crossref PubMed Scopus (21) Google Scholar). The study of STGD and other hereditary macular dystrophies may have important implications for the study of AMD, which is the most common cause of irreversible blindness among elderly individuals in the United States. Historically, the genetic study of AMD has been limited by the clinical heterogeneity, late onset, and multifactorial etiology of the disease (Heiba et al. Heiba et al., 1994Heiba IM Elston RC Klein BEK Klein R Sibling correlations and segregation analysis of age-related maculopathy: the Beaver Dam Study.Genet Epidemiol. 1994; 11: 51-67Crossref PubMed Scopus (224) Google Scholar; Seddon et al. Seddon et al., 1996Seddon JM Willett WC Speizer FE Hankinson SE A prospective study of cigarette smoking and age-related macular degeneration in women.JAMA. 1996; 276: 1141-1146Crossref PubMed Google Scholar, Seddon et al., 1997Seddon JM Ajani UA Mitchell BD Familial aggregation of age-related maculopathy.Am J Ophthalmol. 1997; 123: 199-206Abstract Full Text PDF PubMed Scopus (321) Google Scholar). STGD provides a useful model for the genetic and molecular study of macular degeneration, because of its numerous phenotypic and histopathological similarities to AMD, including progressively decreased vision, atrophy of the macula and retinal-pigment epithelium, dysfunction of retinal photoreceptors, and accumulation of debris within the retinal-pigment epithelium (Young Young, 1987Young RW Pathophysiology of age-related macular degeneration.Surv Ophthalmol. 1987; 31: 291-306Abstract Full Text PDF PubMed Scopus (489) Google Scholar). In light of these similarities, it is reasonable to hypothesize that the genetic basis and pathogenesis of Stargardt-like macular dystrophy may be related to those of certain subsets of AMD. Consistent with this hypothesis is a recent report that certain ABCR sequence changes are found more commonly in persons with AMD (Allikmets et al. Allikmets et al., 1997aAllikmets R Shroyer NF Singh N Seddon JM Lewis RA Bernstein PS Peiffer A et al.Mutation of the Stargardt disease gene (ABCR) in age-related macular degeneration.Science. 1997a; 277: 1805-1807Crossref PubMed Scopus (721) Google Scholar; van Driel et al. van Driel et al., 1998van Driel MA Maugeri A Klevering BJ Hoyng CB Cremers FPM ABCR unites what ophthalmologists divide(s).Ophthalmic Genet. 1998; 19: 117-122Crossref PubMed Scopus (97) Google Scholar), although these data remain controversial (Dryja et al. Dryja et al., 1998Dryja TP Briggs CE Berson EL Rosenfeld PJ Abitbol M ABCR gene and age-related macular degeneration.Science. 1998; 279: 1107(http://www.sciencemag.org/cgi/content/full/279/5354/1107a)Crossref Google Scholar; Klaver et al. Klaver et al., 1998Klaver CCW Assink JJM Bergen AAB van Duijin CM ABCR and age-related macular degeneration.Science. 1998; 279: 1107(http://www.sciencemag.org/cgi/content/full/279/5354/1107a)Crossref Google Scholar; Stone et al. Stone et al., 1998Stone EM Webster AR Vandenburgh K Streb LM Hockey RR Lotery AJ Sheffield VC Allelic variation in ABCR associated with Stargardt disease but not age-related macular degeneration.Nat Genet. 1998; 20: 328-329Crossref PubMed Scopus (174) Google Scholar). Cloning of the STGD4 gene, as well as further genetic and molecular study of hereditary macular dystrophies, should provide important insights into the pathogenesis of AMD. Compilation and analysis of other genes involved in macular dystrophies and AMD may eventually produce a more rational classification system for the various forms of macular degeneration. Finally, the discovery of specific genetic alterations in macular degeneration could create opportunities to improve clinical diagnosis and to offer more-effective, targeted therapies for patients. This work was supported by the Howard Hughes Medical Institute and funds from the National Institutes of Health Core Grant; Fight for Sight the Research Division of Prevent Blindness America; Research to Prevent Blindness; the Foundation Fighting Blindness; and the Mrs. Harry S. Duffy Research Fund. The authors wish to thank J. Zawistowski and M. Kerrigan for their technical assistance, S. Coldfield and J. Sunness for performing the electroretinograms, and J. Seddon for his photographic expertise. The generosity and cooperation of the family members who participated in the study is particularly appreciated." @default.
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• W1991804865 date "1999-05-01" @default.
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• W1991804865 title "A New Locus for Autosomal Dominant Stargardt-Like Disease Maps to Chromosome 4" @default.
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• W1991804865 doi "https://doi.org/10.1086/302377" @default.
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