A subgroup of age-related macular degeneration is associated with mono-allelic sequence variants in the ABCA4 gene

Lars G. Fritsche, Monika Fleckenstein, Britta S. Fiebig, Steffen Schmitz-Valckenberg, Almut Bindewald-Wittich, Claudia N. Keilhauer, Agnes B. Renner, Friederike Mackensen, Andreas Mößner, Daniel Pauleikhoff, Christine Adrion, Ulrich Mansmann, Hendrik P N Scholl, Frank G. Holz, Bernhard H F Weber

Research output: Contribution to journalArticle

Abstract

PURPOSE. Age-related macular degeneration (AMD) is a heterogeneous condition of high prevalence and complex etiology involving genetic as well as environmental factors. By fundus autofluorescence (FAF) imaging, AMD can be classified into several distinct phenotypes, with one subgroup characterized by fine granular pattern with peripheral punctate spots (GPS[+]). Some features of GPS[+] overlap with Stargardt disease (STGD1), a recessive macular dystrophy caused by biallelic sequence variants in the ATP-binding cassette transporter 4 (ABCA4) gene. The aim of this study was to investigate the role of ABCA4 in GPS[+]. METHODS. The ABCA4 gene was sequenced in 25 patients with the GPS[+] phenotype and 29 with geographic atrophy (GA)- AMD but no signs of GPS (GPS[-]). In addition, frequencies of risk-increasing alleles at three known AMD susceptibility loci, including complement factor H (CFH), age-related maculopathy susceptibility 2 (ARMS2), and complement component 3 (C3), were evaluated. RESULTS. We demonstrate that GPS[+] is associated significantly with monoallelic ABCA4 sequence variants. Moreover, frequencies of AMD risk-increasing alleles at CFH, ARMS2, and C3 are similar in GPS[+] and STGD1 patients, with risk allele frequencies in both subcategories comparable to populationbased control individuals estimated from 3,510 individuals from the NHLBI Exome Sequencing Project. CONCLUSIONS. Our data suggest that the GPS[+] phenotype is accounted for by monoallelic variants in ABCA4 and unlikely by the well-established AMD risk-increasing alleles at CFH, ARMS2, and C3. These findings provide support for a complex role of ABCA4 in the etiology of a minor proportion of patients with AMD.

Original languageEnglish (US)
Pages (from-to)2112-2118
Number of pages7
JournalInvestigative Ophthalmology and Visual Science
Volume53
Issue number4
DOIs
StatePublished - Apr 2012

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ATP-Binding Cassette Transporters
Macular Degeneration
Complement Factor H
Genes
Alleles
Phenotype
Geographic Atrophy
Exome
National Heart, Lung, and Blood Institute (U.S.)
Complement C3
Optical Imaging
Gene Frequency

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

Fritsche, L. G., Fleckenstein, M., Fiebig, B. S., Schmitz-Valckenberg, S., Bindewald-Wittich, A., Keilhauer, C. N., ... Weber, B. H. F. (2012). A subgroup of age-related macular degeneration is associated with mono-allelic sequence variants in the ABCA4 gene. Investigative Ophthalmology and Visual Science, 53(4), 2112-2118. https://doi.org/10.1167/iovs.11-8475

A subgroup of age-related macular degeneration is associated with mono-allelic sequence variants in the ABCA4 gene. / Fritsche, Lars G.; Fleckenstein, Monika; Fiebig, Britta S.; Schmitz-Valckenberg, Steffen; Bindewald-Wittich, Almut; Keilhauer, Claudia N.; Renner, Agnes B.; Mackensen, Friederike; Mößner, Andreas; Pauleikhoff, Daniel; Adrion, Christine; Mansmann, Ulrich; Scholl, Hendrik P N; Holz, Frank G.; Weber, Bernhard H F.

In: Investigative Ophthalmology and Visual Science, Vol. 53, No. 4, 04.2012, p. 2112-2118.

Research output: Contribution to journalArticle

Fritsche, LG, Fleckenstein, M, Fiebig, BS, Schmitz-Valckenberg, S, Bindewald-Wittich, A, Keilhauer, CN, Renner, AB, Mackensen, F, Mößner, A, Pauleikhoff, D, Adrion, C, Mansmann, U, Scholl, HPN, Holz, FG & Weber, BHF 2012, 'A subgroup of age-related macular degeneration is associated with mono-allelic sequence variants in the ABCA4 gene', Investigative Ophthalmology and Visual Science, vol. 53, no. 4, pp. 2112-2118. https://doi.org/10.1167/iovs.11-8475
Fritsche LG, Fleckenstein M, Fiebig BS, Schmitz-Valckenberg S, Bindewald-Wittich A, Keilhauer CN et al. A subgroup of age-related macular degeneration is associated with mono-allelic sequence variants in the ABCA4 gene. Investigative Ophthalmology and Visual Science. 2012 Apr;53(4):2112-2118. https://doi.org/10.1167/iovs.11-8475
Fritsche, Lars G. ; Fleckenstein, Monika ; Fiebig, Britta S. ; Schmitz-Valckenberg, Steffen ; Bindewald-Wittich, Almut ; Keilhauer, Claudia N. ; Renner, Agnes B. ; Mackensen, Friederike ; Mößner, Andreas ; Pauleikhoff, Daniel ; Adrion, Christine ; Mansmann, Ulrich ; Scholl, Hendrik P N ; Holz, Frank G. ; Weber, Bernhard H F. / A subgroup of age-related macular degeneration is associated with mono-allelic sequence variants in the ABCA4 gene. In: Investigative Ophthalmology and Visual Science. 2012 ; Vol. 53, No. 4. pp. 2112-2118.
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abstract = "PURPOSE. Age-related macular degeneration (AMD) is a heterogeneous condition of high prevalence and complex etiology involving genetic as well as environmental factors. By fundus autofluorescence (FAF) imaging, AMD can be classified into several distinct phenotypes, with one subgroup characterized by fine granular pattern with peripheral punctate spots (GPS[+]). Some features of GPS[+] overlap with Stargardt disease (STGD1), a recessive macular dystrophy caused by biallelic sequence variants in the ATP-binding cassette transporter 4 (ABCA4) gene. The aim of this study was to investigate the role of ABCA4 in GPS[+]. METHODS. The ABCA4 gene was sequenced in 25 patients with the GPS[+] phenotype and 29 with geographic atrophy (GA)- AMD but no signs of GPS (GPS[-]). In addition, frequencies of risk-increasing alleles at three known AMD susceptibility loci, including complement factor H (CFH), age-related maculopathy susceptibility 2 (ARMS2), and complement component 3 (C3), were evaluated. RESULTS. We demonstrate that GPS[+] is associated significantly with monoallelic ABCA4 sequence variants. Moreover, frequencies of AMD risk-increasing alleles at CFH, ARMS2, and C3 are similar in GPS[+] and STGD1 patients, with risk allele frequencies in both subcategories comparable to populationbased control individuals estimated from 3,510 individuals from the NHLBI Exome Sequencing Project. CONCLUSIONS. Our data suggest that the GPS[+] phenotype is accounted for by monoallelic variants in ABCA4 and unlikely by the well-established AMD risk-increasing alleles at CFH, ARMS2, and C3. These findings provide support for a complex role of ABCA4 in the etiology of a minor proportion of patients with AMD.",
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T1 - A subgroup of age-related macular degeneration is associated with mono-allelic sequence variants in the ABCA4 gene

AU - Fritsche, Lars G.

AU - Fleckenstein, Monika

AU - Fiebig, Britta S.

AU - Schmitz-Valckenberg, Steffen

AU - Bindewald-Wittich, Almut

AU - Keilhauer, Claudia N.

AU - Renner, Agnes B.

AU - Mackensen, Friederike

AU - Mößner, Andreas

AU - Pauleikhoff, Daniel

AU - Adrion, Christine

AU - Mansmann, Ulrich

AU - Scholl, Hendrik P N

AU - Holz, Frank G.

AU - Weber, Bernhard H F

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N2 - PURPOSE. Age-related macular degeneration (AMD) is a heterogeneous condition of high prevalence and complex etiology involving genetic as well as environmental factors. By fundus autofluorescence (FAF) imaging, AMD can be classified into several distinct phenotypes, with one subgroup characterized by fine granular pattern with peripheral punctate spots (GPS[+]). Some features of GPS[+] overlap with Stargardt disease (STGD1), a recessive macular dystrophy caused by biallelic sequence variants in the ATP-binding cassette transporter 4 (ABCA4) gene. The aim of this study was to investigate the role of ABCA4 in GPS[+]. METHODS. The ABCA4 gene was sequenced in 25 patients with the GPS[+] phenotype and 29 with geographic atrophy (GA)- AMD but no signs of GPS (GPS[-]). In addition, frequencies of risk-increasing alleles at three known AMD susceptibility loci, including complement factor H (CFH), age-related maculopathy susceptibility 2 (ARMS2), and complement component 3 (C3), were evaluated. RESULTS. We demonstrate that GPS[+] is associated significantly with monoallelic ABCA4 sequence variants. Moreover, frequencies of AMD risk-increasing alleles at CFH, ARMS2, and C3 are similar in GPS[+] and STGD1 patients, with risk allele frequencies in both subcategories comparable to populationbased control individuals estimated from 3,510 individuals from the NHLBI Exome Sequencing Project. CONCLUSIONS. Our data suggest that the GPS[+] phenotype is accounted for by monoallelic variants in ABCA4 and unlikely by the well-established AMD risk-increasing alleles at CFH, ARMS2, and C3. These findings provide support for a complex role of ABCA4 in the etiology of a minor proportion of patients with AMD.

AB - PURPOSE. Age-related macular degeneration (AMD) is a heterogeneous condition of high prevalence and complex etiology involving genetic as well as environmental factors. By fundus autofluorescence (FAF) imaging, AMD can be classified into several distinct phenotypes, with one subgroup characterized by fine granular pattern with peripheral punctate spots (GPS[+]). Some features of GPS[+] overlap with Stargardt disease (STGD1), a recessive macular dystrophy caused by biallelic sequence variants in the ATP-binding cassette transporter 4 (ABCA4) gene. The aim of this study was to investigate the role of ABCA4 in GPS[+]. METHODS. The ABCA4 gene was sequenced in 25 patients with the GPS[+] phenotype and 29 with geographic atrophy (GA)- AMD but no signs of GPS (GPS[-]). In addition, frequencies of risk-increasing alleles at three known AMD susceptibility loci, including complement factor H (CFH), age-related maculopathy susceptibility 2 (ARMS2), and complement component 3 (C3), were evaluated. RESULTS. We demonstrate that GPS[+] is associated significantly with monoallelic ABCA4 sequence variants. Moreover, frequencies of AMD risk-increasing alleles at CFH, ARMS2, and C3 are similar in GPS[+] and STGD1 patients, with risk allele frequencies in both subcategories comparable to populationbased control individuals estimated from 3,510 individuals from the NHLBI Exome Sequencing Project. CONCLUSIONS. Our data suggest that the GPS[+] phenotype is accounted for by monoallelic variants in ABCA4 and unlikely by the well-established AMD risk-increasing alleles at CFH, ARMS2, and C3. These findings provide support for a complex role of ABCA4 in the etiology of a minor proportion of patients with AMD.

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