Letter abstract
Nature Genetics 40, 892 - 896 (2008)
Published online: 30 May 2008 | doi:10.1038/ng.170
Age-related macular degeneration is associated with an unstable ARMS2 (LOC387715) mRNA
Lars G Fritsche1,4, Thomas Loenhardt1,4, Andreas Janssen1, Sheila A Fisher2, Andrea Rivera1, Claudia N Keilhauer3 & Bernhard H F Weber1
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.
- Institute of Human Genetics, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany.
- Department of Medical and Molecular Genetics, King's College and St Thomas' Hospitals, London, WC2R 2LS, UK.
- Department of Ophthalmology, University of Wuerzburg, 97080 Wuerzburg, Germany.
- These authors contributed equally to this work.
Correspondence to: Bernhard H F Weber1 e-mail: bweb@klinik.uni-regensburg.de
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