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The ABCA4 2588G>C Stargardt mutation: single origin and increasing frequency from South-West to North-East Europe.

https://arctichealth.org/en/permalink/ahliterature50771
Source
Eur J Hum Genet. 2002 Mar;10(3):197-203
Publication Type
Article
Date
Mar-2002
Author
Alessandra Maugeri
Kris Flothmann
Nadine Hemmrich
Sofie Ingvast
Paula Jorge
Eva Paloma
Reshma Patel
Jean-Michel Rozet
Jaana Tammur
Francesco Testa
Susana Balcells
Alan C Bird
Han G Brunner
Carel B Hoyng
Andres Metspalu
Francesca Simonelli
Rando Allikmets
Shomi S Bhattacharya
Michele D'Urso
Roser Gonzàlez-Duarte
Josseline Kaplan
Gerard J te Meerman
Rosário Santos
Marianne Schwartz
Guy Van Camp
Claes Wadelius
Bernhard H F Weber
Frans P M Cremers
Author Affiliation
Department of Human Genetics, University Medical Center Nijmegen, Nijmegen, The Netherlands. a.maugeri@antrg.azn.nl
Source
Eur J Hum Genet. 2002 Mar;10(3):197-203
Date
Mar-2002
Language
English
Publication Type
Article
Keywords
ATP-Binding Cassette Transporters - genetics
Alleles
Base Sequence
Europe
Gene Frequency
Heterozygote
Humans
Molecular Sequence Data
Mutation
Point Mutation
Research Support, Non-U.S. Gov't
United States
Abstract
Inherited retinal dystrophies represent the most important cause of vision impairment in adolescence, affecting approximately 1 out of 3000 individuals. Mutations of the photoreceptor-specific gene ABCA4 (ABCR) are a common cause of retinal dystrophy. A number of mutations have been repeatedly reported for this gene, notably the 2588G>C mutation which is frequent in both patients and controls. Here we ascertained the frequency of the 2588G>C mutation in a total of 2343 unrelated random control individuals from 11 European countries and 241 control individuals from the US, as well as in 614 patients with STGD both from Europe and the US. We found an overall carrier frequency of 1 out of 54 in Europe, compared with 1 out of 121 in the US, confirming that the 2588G>C ABCA4 mutation is one of the most frequent autosomal recessive mutations in the European population. Carrier frequencies show an increasing gradient in Europe from South-West to North-East. The lowest carrier frequency, 0 out of 199 (0%), was found in Portugal; the highest, 11 out of 197 (5.5%), was found in Sweden. Haplotype analysis in 16 families segregating the 2588G>C mutation showed four intragenic polymorphisms invariably present in all 16 disease chromosomes and sharing of the same allele for several markers flanking the ABCA4 locus in most of the disease chromosomes. These results indicate a single origin of the 2588G>C mutation which, to our best estimate, occurred between 2400 and 3000 years ago.
PubMed ID
11973624 View in PubMed
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A rare nonsynonymous sequence variant in C3 is associated with high risk of age-related macular degeneration.

https://arctichealth.org/en/permalink/ahliterature107251
Source
Nat Genet. 2013 Nov;45(11):1371-4
Publication Type
Article
Date
Nov-2013
Author
Hannes Helgason
Patrick Sulem
Maheswara R Duvvari
Hongrong Luo
Gudmar Thorleifsson
Hreinn Stefansson
Ingileif Jonsdottir
Gisli Masson
Daniel F Gudbjartsson
G Bragi Walters
Olafur Th Magnusson
Augustine Kong
Thorunn Rafnar
Lambertus A Kiemeney
Frederieke E Schoenmaker-Koller
Ling Zhao
Camiel J F Boon
Yaojun Song
Sascha Fauser
Michelle Pei
Tina Ristau
Shirrina Patel
Sandra Liakopoulos
Johannes P H van de Ven
Carel B Hoyng
Henry Ferreyra
Yaou Duan
Paul S Bernstein
Asbjorg Geirsdottir
Gudleif Helgadottir
Einar Stefansson
Anneke I den Hollander
Kang Zhang
Fridbert Jonasson
Haraldur Sigurdsson
Unnur Thorsteinsdottir
Kari Stefansson
Author Affiliation
1] deCODE Genetics/Amgen, Reykjavik, Iceland. [2] School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland. [3].
Source
Nat Genet. 2013 Nov;45(11):1371-4
Date
Nov-2013
Language
English
Publication Type
Article
Keywords
Amino Acid Substitution
Base Sequence
Complement Activation - genetics
Complement C3 - genetics
Complement C3b - immunology - metabolism
Complement Factor H - immunology - metabolism
Gene Frequency
Genetic Predisposition to Disease
Genetic Variation
Genome-Wide Association Study
Genotype
Humans
Iceland
Macular Degeneration - genetics
Polymorphism, Single Nucleotide
Risk
Sequence Analysis, DNA
Abstract
Through whole-genome sequencing of 2,230 Icelanders, we detected a rare nonsynonymous SNP (minor allele frequency = 0.55%) in the C3 gene encoding a p.Lys155Gln substitution in complement factor 3, which, following imputation into a set of Icelandic cases with age-related macular degeneration (AMD) and controls, associated with disease (odds ratio (OR) = 3.45; P = 1.1 × 10(-7)). This signal is independent of the previously reported common SNPs in C3 encoding p.Pro314Leu and p.Arg102Gly that associate with AMD. The association of p.Lys155Gln was replicated in AMD case-control samples of European ancestry with OR = 4.22 and P = 1.6 × 10(-10), resulting in OR = 3.65 and P = 8.8 × 10(-16) for all studies combined. In vitro studies have suggested that the p.Lys155Gln substitution reduces C3b binding to complement factor H, potentially creating resistance to inhibition by this factor. This resistance to inhibition in turn is predicted to result in enhanced complement activation.
PubMed ID
24036950 View in PubMed
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