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

• DOI: 10.1038/ng.170
• Publication Date: 2008-05-30T12:03:15Z
• Authors: Lars G Fritsche; Thomas Loenhardt; Andreas Janssen; Sheila A Fisher; Andrea Rivera; Claudia N Keilhauer; Bernhard H F Weber
• Keywords: Aged, 80 and over; Male; Base Sequence; Genotype; RNA Stability; DNA Mutational Analysis; Molecular Sequence Data; 610; Proteins; High-Temperature Requirement A Serine Peptidase 1; Models, Biological; Polymorphism, Single Nucleotide; Linkage Disequilibrium; Macular Degeneration; 03 medical and health sciences; 0302 clinical medicine; Gene Frequency; Case-Control Studies; Humans; Female; Amino Acid Sequence; RNA, Messenger; Aged

Age-related macular degeneration (AMD) is a prevalent multifactorial disorder of the central retina. Genetic variants at two chromosomal loci, 1q31 and 10q26, confer major disease risks, together accounting for more than 50% of AMD pathology. Signals at 10q26 center over two nearby genes, ARMS2 (age-related maculopathy susceptibility 2, also known as LOC387715) and HTRA1 (high-temperature requirement factor A1), 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 findings, 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.