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

Nat Genet. 2008 Jul;40(7):892-6. doi: 10.1038/ng.170. Epub 2008 May 30.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Amino Acid Sequence
  • Base Sequence
  • Case-Control Studies
  • DNA Mutational Analysis
  • Female
  • Gene Frequency
  • Genotype
  • High-Temperature Requirement A Serine Peptidase 1
  • Humans
  • Linkage Disequilibrium
  • Macular Degeneration / genetics*
  • Male
  • Models, Biological
  • Molecular Sequence Data
  • Polymorphism, Single Nucleotide
  • Proteins / genetics*
  • Proteins / metabolism
  • RNA Stability / genetics
  • RNA Stability / physiology*
  • RNA, Messenger / metabolism
  • Serine Endopeptidases / genetics
  • Tissue Distribution


  • ARMS2 protein, human
  • Proteins
  • RNA, Messenger
  • High-Temperature Requirement A Serine Peptidase 1
  • HtrA1 protein, human
  • Serine Endopeptidases

Associated data

  • GENBANK/EU427539
  • RefSeq/NM_001099667
  • RefSeq/NM_002775