Open AccessJournal Article
An analysis of allelic variation in the ABCA4 gene
Andrew R. Webster,Elise Heon,Andrew J. Lotery,Kimberlie Vandenburgh,Thomas L. Casavant,Kean T. Oh,Gretel Beck,Gerald A. Fishman,Byron L. Lam,Alex Levin,John R. Heckenlively,Samuel G. Jacobson,Richard G. Weleber,Val C. Sheffield,Edwin M. Stone +14 more
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TLDR
The nucleotide diversity of the ABCA4 coding region, a collective measure of the number and prevalence of polymorphic sites in a region of DNA, was found to be 1.28, a value that is 9 to 400 times greater than that of two other macular disease genes that were examined in a similar fashion.Abstract:
PURPOSE. To assess the allelic variation of the ATP-binding transporter protein (ABCA4). METHODS. A combination of single-strand conformation polymorphism (SSCP) and automated DNA sequencing was used to systematically screen this gene for sequence variations in 374 unrelated probands with a clinical diagnosis of Stargardt disease, 182 patients with age-related macular degeneration (AMD), and 96 normal subjects. RESULTS. There was no significant difference in the proportion of any single variant or class of variant between the control and AMD groups. In contrast, truncating variants, amino acid substitutions, synonymous codon changes, and intronic variants were significantly enriched in patients with Stargardt disease when compared with their presence in subjects without Stargardt disease (Kruskal-Wallis P < 0.0001 for each variant group). Overall, there were 2480 instances of 213 different variants in the ABCA4 gene, including 589 instances of 97 amino acid substitutions, and 45 instances of 33 truncating variants. CONCLUSIONS. Of the 97 amino acid substitutions, 11 occurred at a frequency that made them unlikely to be high-penetrance recessive disease-causing variants (HPRDCV). After accounting for variants in cis, one or more changes that were compatible with HPRDCV were found on 35% of all Stargardt-associated alleles overall. The nucleotide diversity of the ABCA4 coding region, a collective measure of the number and prevalence of polymorphic sites in a region of DNA, was found to be 1.28, a value that is 9 to 400 times greater than that of two other macular disease genes that were examined in a similar fashion (VMD2 and EFEMP1).read more
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Age-related macular degeneration: etiology, pathogenesis, and therapeutic strategies.
Jayakrishna Ambati,Jayakrishna Ambati,Balamurali K. Ambati,Balamurali K. Ambati,Sonia H Yoo,Sonia H Yoo,Sean Ianchulev,Anthony P. Adamis +7 more
TL;DR: Transgenic and knockout studies have provided important mechanistic insights into the development of choroidal neovascularization, the principal cause of vision loss in age-related macular degeneration, and this in turn has culminated in preclinical and clinical trials of directed molecular interventions.
Journal ArticleDOI
Missense variations in the fibulin 5 gene and age-related macular degeneration.
Edwin M. Stone,Terry A. Braun,Stephen R. Russell,Markus H. Kuehn,Andrew J. Lotery,Paula A. Moore,C.G. Eastman,Thomas L. Casavant,Val C. Sheffield +8 more
TL;DR: Seven of the 402 patients with AMD had amino acid-altering sequence variations in the fibulin 5 gene, whereas none were observed among 429 control subjects, which suggests that several of these variations may also be involved in AMD.
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The Genetics of Age-Related Macular Degeneration: A Review of Progress to Date
TL;DR: In this article, a major risk variant within the complement factor H gene (CFH) was identified, and recent reports suggest that PLEKHA1/LOC387715 and the BF/C2 regions may be major risk loci for AMD as well.
Journal ArticleDOI
Regulation of gene expression in the mammalian eye and its relevance to eye disease
Todd E. Scheetz,Kwang-Youn Kim,Ruth E. Swiderski,Alisdair R. Philp,Terry A. Braun,Kevin L. Knudtson,Anne M. Dorrance,Gerald F. DiBona,Jian Huang,Thomas L. Casavant,Val C. Sheffield,Edwin M. Stone +11 more
TL;DR: A pairwise analysis of gene expression was performed to identify genes that are regulated in a coordinated manner and used this approach to validate two previously undescribed genes involved in the human disease Bardet–Biedl syndrome.
Journal ArticleDOI
Genotyping microarray (gene chip) for the ABCR (ABCA4) gene.
K. Jaakson,Jana Zernant,Jana Zernant,Maigi Külm,Amy Hutchinson,Neeme Tõnisson,D. Glavac,Metka Ravnik-Glavač,M. Hawlina,M.R. Meltzer,Rafael C. Caruso,Francesco Testa,Alessandra Maugeri,Carel B. Hoyng,Peter Gouras,Francesca Simonelli,Richard A. Lewis,James R. Lupski,F.P.M. Cremers,Rando Allikmets +19 more
TL;DR: A genotyping microarray for ABCR that includes all ∼400 disease‐associated and other variants currently described, enabling simultaneous detection of all known ABCR variants and is a robust, cost‐effective, and comprehensive screening tool for variation in one gene in which mutations are responsible for a substantial fraction of retinal disease.
References
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Journal ArticleDOI
Mathematical model for studying genetic variation in terms of restriction endonucleases
Masatoshi Nei,Wen-Hsiung Li +1 more
TL;DR: A mathematical model for the evolutionary change of restriction sites in mitochondrial DNA is developed and a measure called "nucleotide diversity" is proposed to express the degree of polymorphism in a population at the nucleotide level.
Journal ArticleDOI
Distantly related sequences in the alpha- and beta-subunits of ATP synthase, myosin, kinases and other ATP-requiring enzymes and a common nucleotide binding fold.
TL;DR: Related sequences in both alpha and beta and in other enzymes that bind ATP or ADP in catalysis help to identify regions contributing to an adenine nucleotide binding fold in both ATP synthase subunits.
Journal ArticleDOI
Detection of polymorphisms of human DNA by gel electrophoresis as single-strand conformation polymorphisms
TL;DR: The mobility shift analysis of single-stranded DNAs on neutral polyacrylamide gel electrophoresis to detect DNA polymorphisms was developed and SSCPs were found to be allelic variants of true Mendelian traits, and therefore they should be useful genetic markers.
Journal ArticleDOI
Identification of the cystic fibrosis gene: Chromosome walking and jumping
Johanna M. Rommens,Michael C. Iannuzzi,Batsheva Kerem,Mitchell L. Drumm,Georg Melmer,Michael Dean,Richard Rozmahel,Jeffery L. Cole,Dara Kennedy,Noriko Hidaka,Martha Zsiga,Manuel Buchwald,John R. Riordan,Lap-Chee Tsui,Francis S. Collins +14 more
TL;DR: Several transcribed sequences and conserved segments were identified in this cloned region and one corresponds to the cystic fibrosis gene and spans approximately 250,000 base pairs of genomic DNA.
Journal ArticleDOI
An international classification and grading system for age-related maculopathy and age-related macular degeneration
Alan C. Bird,Neil M. Bressler,Susan B. Bressler,I H Chisholm,Gabriel Coscas,M.D. Davis,P.T.V.M. de Jong,Caroline C W Klaver,Barbara E.K. Klein,Ronald Klein,Philip B. Mitchell,J.P. Sarks,S.H. Sarks,Gisèle Soubrane,Hugh R. Taylor,Johannes R. Vingerling +15 more
TL;DR: A common detection and classification system is needed for epidemiologic studies of age-related maculopathy (ARM) and such a grading scheme for ARM is described in this paper.