Abstract
Age-related macular degeneration (AMD) is a prevalent multifactorial disorder of the central retina1,2,3. Genetic variants at two chromosomal loci, 1q31 and 10q26, confer major disease risks, together accounting for more than 50% of AMD pathology4,5,6,7,8,9. Signals at 10q26 center over two nearby genes, ARMS2 (age-related maculopathy susceptibility 2, also known as LOC387715)8,9 and HTRA1 (high-temperature requirement factor A1)10,11, suggesting two equally probable candidates. Here we show that a deletion-insertion polymorphism in ARMS2 (NM_001099667.1:c.*372_815del443ins54) is strongly associated with AMD, directly affecting the transcript by removing the polyadenylation signal and inserting a 54-bp element known to mediate rapid mRNA turnover. As a consequence, expression of ARMS2 in homozygous carriers of the indel variant is not detectable. Confirming previous findings12, we demonstrate a mitochondrial association of the normal protein and further define its retinal localization to the ellipsoid region of the photoreceptors. Our data suggest that ARMS2 has a key role in AMD, possibly through mitochondria-related pathways.
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Acknowledgements
We are grateful to the individuals with AMD and the control subjects for their participation in this study; G. Huber for help with placental samples; P. Lichtner and T. Meitinger for SNP genotyping, R.S. Molday (Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, Canada) for kindly sharing monoclonal antibodies RS1-3R10 and Rho-1D4, F.R. Rauscher (Institute of Human Genetics, University of Regensburg, Germany) for providing ARMS2 cDNA clones of isoforms 1 and 2, and D. Wagner for technical assistance. This work was supported in part by grants to B.H.F.W. from the German Research Foundation (DFG), the Ruth and Milton Steinbach Foundation New York (B.H.F.W.) and the Alcon Research Institute.
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L.G.F., T.L., A.J. and A.R. carried out all experimental studies. Specifically, L.G.F. participated in conception and design of the association study, was involved in all aspects of genotyping and data analysis and drafted the manuscript. T.L. made major contributions to the generation of ARMS2 antibodies and was responsible for all aspects of the protein work. A.J. carried out the immunohistochemistry studies. A.R. was involved in data acquisition and the characterization of ARMS2 isoforms and carried out the RNA work. S.A.F. performed the statistical analyses and critically revised the manuscript. C.N.K. recruited the individuals with AMD and the controls and collected the peripheral blood samples. B.H.F.W. conceived of the study, participated in its design and coordination and finalized the manuscript. All authors read and approved the final text.
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Fritsche, L., Loenhardt, T., Janssen, A. et al. Age-related macular degeneration is associated with an unstable ARMS2 (LOC387715) mRNA. Nat Genet 40, 892–896 (2008). https://doi.org/10.1038/ng.170
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DOI: https://doi.org/10.1038/ng.170
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