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

L G Fritsche; T Loenhardt; A Janssen; S A Fisher; A Rivera; C N Keilhauer; B H F Weber

doi:10.1038/ng.170

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

L G Fritsche, T Loenhardt, A Janssen, S A Fisher, A Rivera, C N Keilhauer, B H F Weber

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Abstract

Age-related macular degeneration (AMD) is a prevalent multifactorial disorder of the central retina(1-3). Genetic variants at two chromosomal loci, 1q31 and 10q26, confer major disease risks, together accounting for more than 50% of AMD pathology(4-9). 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 findings(12), 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

Original language	English
Pages (from-to)	892 - 896
Number of pages	5
Journal	Nature Genetics
Volume	40
Issue number	7
DOIs	https://doi.org/10.1038/ng.170
Publication status	Published - Jul 2008

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@article{78f05bed62d448ebbea15c01bc91e8d1,

title = "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 retina(1-3). Genetic variants at two chromosomal loci, 1q31 and 10q26, confer major disease risks, together accounting for more than 50% of AMD pathology(4-9). 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 findings(12), 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",

author = "Fritsche, {L G} and T Loenhardt and A Janssen and Fisher, {S A} and A Rivera and Keilhauer, {C N} and Weber, {B H F}",

year = "2008",

month = jul,

doi = "10.1038/ng.170",

language = "English",

volume = "40",

pages = "892 -- 896",

journal = "Nature Genetics",

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T1 - Age-related macular degeneration is associated with an unstable ARMS2 (LOC387715) mRNA

AU - Fritsche, L G

AU - Loenhardt, T

AU - Janssen, A

AU - Fisher, S A

AU - Rivera, A

AU - Keilhauer, C N

AU - Weber, B H F

PY - 2008/7

Y1 - 2008/7

N2 - Age-related macular degeneration (AMD) is a prevalent multifactorial disorder of the central retina(1-3). Genetic variants at two chromosomal loci, 1q31 and 10q26, confer major disease risks, together accounting for more than 50% of AMD pathology(4-9). 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 findings(12), 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

AB - Age-related macular degeneration (AMD) is a prevalent multifactorial disorder of the central retina(1-3). Genetic variants at two chromosomal loci, 1q31 and 10q26, confer major disease risks, together accounting for more than 50% of AMD pathology(4-9). 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 findings(12), 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

U2 - 10.1038/ng.170

DO - 10.1038/ng.170

M3 - Article

SN - 1546-1718

VL - 40

SP - 892

EP - 896

JO - Nature Genetics

JF - Nature Genetics

IS - 7

ER -

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

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