title: Identification of a Nuclear Respiratory Factor 1 Recognition Motif in the Apolipoprotein E Variant APOE4 linked to Alzheimer's Disease.
abstract: Alzheimer's disease affects tens of millions of people worldwide and its prevalence continues to rise. It is caused by a combination of a subject's heredity, environment, lifestyle, and medical condition. The most significant genetic risk factor for late onset Alzheimer's disease is a variant of the apolipoprotein E gene, APOE4. Here we show that the single nucleotide polymorphism rs429358 that defines APOE4 is located in a short sequence motif repeated several times within exon 4 of apolipoprotein E, reminiscent of the structure of transcriptional enhancers. A JASPAR database search predicts that the T to C transition in rs429358 generates a binding motif for nuclear respiratory factor NRF1. This site appears to be part of a binding site cluster for this transcription factor on exon 4 of APOE. This de novo NRF1 binding site has therefore the potential to affect the expression of multiple genes in its genomic vicinity. Our in silico analysis, suggesting a novel function for APOE4 at the DNA level, offers a potential mechanism for the observed tissue specific neurodegeneration and the role of environmental factors in Alzheimer's disease etiology.
authors.affiliation: Selonterra LLC, 1025 Alameda de las Pulgas, Suite 126, Belmont CA 94002, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Urfer-Buchwalder
authors.affiliation: Selonterra LLC, 1025 Alameda de las Pulgas, Suite 126, Belmont CA 94002, USA.
authors.forename: Roman
authors.initials: R
authors.lastname: Urfer
mesh_terms: D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism*; D053327:Apolipoprotein E4 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D001665:Binding Sites; D005091:Exons; D005786:Gene Expression Regulation; D014644:Genetic Variation; D006801:Humans; D051266:Nuclear Respiratory Factor 1 / Q000378:metabolism*; D059372:Nucleotide Motifs; D020641:Polymorphism, Single Nucleotide; D056510:Position-Specific Scoring Matrices; D011485:Protein Binding
chemical_list: D053327:Apolipoprotein E4; D051266:Nuclear Respiratory Factor 1