Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Age-related macular degeneration is associated with an unstable ARMS2 (LOC387715) mRNA

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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: ARMS2 isoforms and effects of the indel variant on gene expression.
Figure 2: Analysis of ARMS2 protein expression.
Figure 3: Localization of ARMS2 in the human retina.

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Mitchell, P., Smith, W., Attebo, K. & Wang, J.J. Prevalence of age-related maculopathy in Australia. The Blue Mountains Eye Study. Ophthalmology 102, 1450–1460 (1995).

    Article  CAS  PubMed  Google Scholar 

  2. Vingerling, J.R. et al. The prevalence of age-related maculopathy in the Rotterdam Study. Ophthalmology 102, 205–210 (1995).

    Article  CAS  PubMed  Google Scholar 

  3. Seddon, J.M., Ajani, U.A. & Mitchell, B.D. Familial aggregation of age-related maculopathy. Am. J. Ophthalmol. 123, 199–206 (1997).

    Article  CAS  PubMed  Google Scholar 

  4. Klein, R.J. et al. Complement factor H polymorphism in age-related macular degeneration. Science 308, 385–389 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Edwards, A.O. et al. Complement factor H polymorphism and age-related macular degeneration. Science 308, 421–424 (2005).

    Article  CAS  PubMed  Google Scholar 

  6. Haines, J.L. et al. Complement factor H variant increases the risk of age-related macular degeneration. Science 308, 419–421 (2005).

    Article  CAS  PubMed  Google Scholar 

  7. Hageman, G.S. et al. A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc. Natl. Acad. Sci. USA 102, 7227–7232 (2005).

    Article  CAS  PubMed  Google Scholar 

  8. Jakobsdottir, J. et al. Susceptibility genes for age-related maculopathy on chromosome 10q26. Am. J. Hum. Genet. 77, 389–407 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Rivera, A. et al. Hypothetical LOC387715 is a second major susceptibility gene for age-related macular degeneration, contributing independently of complement factor H to disease risk. Hum. Mol. Genet. 14, 3227–3236 (2005).

    Article  CAS  PubMed  Google Scholar 

  10. Dewan, A. et al. HTRA1 promoter polymorphism in wet age-related macular degeneration. Science 314, 989–992 (2006).

    Article  CAS  PubMed  Google Scholar 

  11. Yang, Z. et al. A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration. Science 314, 992–993 (2006).

    Article  CAS  PubMed  Google Scholar 

  12. Kanda, A. et al. A variant of mitochondrial protein LOC387715/ARMS2, not HTRA1, is strongly associated with age-related macular degeneration. Proc. Natl. Acad. Sci. USA 104, 16227–16232 (2007).

    Article  CAS  PubMed  Google Scholar 

  13. Grau, S. et al. The role of human HtrA1 in arthritic disease. J. Biol. Chem. 281, 6124–6129 (2006).

    Article  CAS  PubMed  Google Scholar 

  14. Khabar, K.S. The AU-rich transcriptome: more than interferons and cytokines, and its role in disease. J. Interferon Cytokine Res. 25, 1–10 (2005).

    Article  CAS  PubMed  Google Scholar 

  15. Barreau, C., Paillard, L. & Osborne, H.B. AU-rich elements and associated factors: are there unifying principles? Nucleic Acids Res. 33, 7138–7150 (2005).

    Article  CAS  PubMed  Google Scholar 

  16. Garneau, N.L., Wilusz, J. & Wilusz, C.J. The highways and byways of mRNA decay. Nat. Rev. Mol. Cell Biol. 8, 113–126 (2007).

    Article  CAS  PubMed  Google Scholar 

  17. Molday, L.L., Hicks, D., Sauer, C.G., Weber, B.H. & Molday, R.S. Expression of X-linked retinoschisis protein RS1 in photoreceptor and bipolar cells. Invest. Ophthalmol. Vis. Sci. 42, 816–825 (2001).

    CAS  PubMed  Google Scholar 

  18. Zeviani, M. & Carelli, V. Mitochondrial disorders. Curr. Opin. Neurol. 20, 564–571 (2007).

    Article  CAS  PubMed  Google Scholar 

  19. Zarbin, M.A. Current concepts in the pathogenesis of age-related macular degeneration. Arch. Ophthalmol. 122, 598–614 (2004).

    Article  PubMed  Google Scholar 

  20. Lin, M.T. & Beal, M.F. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443, 787–795 (2006).

    Article  CAS  PubMed  Google Scholar 

  21. Gabriel, S.B. et al. The structure of haplotype blocks in the human genome. Science 296, 2225–2229 (2002).

    Article  CAS  PubMed  Google Scholar 

  22. Barrett, J.C., Fry, B., Maller, J. & Daly, M.J. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–265 (2005).

    Article  CAS  PubMed  Google Scholar 

  23. Dudbridge, F. Pedigree disequilibrium tests for multilocus haplotypes. Genet. Epidemiol. 25, 115–121 (2003).

    Article  PubMed  Google Scholar 

  24. Dudbridge, F. UNPHASED user guide. Technical Report 5. (MRC Biostatistics Unit, Cambridge, 2006).

  25. Fisher, S.A. et al. Case-control genetic association study of fibulin-6 (FBLN6 or HMCN1) variants in age-related macular degeneration (AMD). Hum. Mutat. 28, 406–413 (2007).

    Article  CAS  PubMed  Google Scholar 

  26. Geysen, H.M., Rodda, S.J., Mason, T.J., Tribbick, G. & Schoofs, P.G. Strategies for epitope analysis using peptide synthesis. J. Immunol. Methods 102, 259–274 (1987).

    Article  CAS  PubMed  Google Scholar 

  27. Fernandez-Vizarra, E., Lopez-Perez, M.J. & Enriquez, J.A. Isolation of biogenetically competent mitochondria from mammalian tissues and cultured cells. Methods 26, 292–297 (2002).

    Article  PubMed  Google Scholar 

  28. Wu, W.W. & Molday, R.S. Defective discoidin domain structure, subunit assembly, and endoplasmic reticulum processing of retinoschisin are primary mechanisms responsible for X-linked retinoschisis. J. Biol. Chem. 278, 28139–28146 (2003).

    Article  CAS  PubMed  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

Authors

Contributions

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.

Corresponding author

Correspondence to Bernhard H F Weber.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1 and 2 and Supplementary Tables 1–5 (PDF 3198 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.170

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing