title: A novel functional low-density lipoprotein receptor-related protein 6 gene alternative splice variant is associated with Alzheimer's disease.
abstract: We previously found that single nucleotide polymorphisms in the low-density lipoprotein receptor-related protein 6 (LRP6) gene are associated with Alzheimer's disease (AD). Here, we studied the posttranscriptional metabolism of the LRP6 message scanning sequentially the 23 LRP6 exons in human tissues and found a novel LRP6 isoform that completely skips exon 3 (LRP6Δ3) in all tissues examined and was also conserved in mice. Expression levels of the LRP6 isoforms were determined in 47 cortical brain messenger (m)RNA samples including 22 AD cases, 11 control subjects, and 14 individuals with other neurological disorders. LRP6Δ3 mRNA levels were significantly augmented in AD brains compared with controls (1.6-fold; p = 0.037) or other pathological samples (2-fold; p = 0.007). Functional analysis in Wnt/β-catenin signaling assays revealed that skipping of exon 3 reduced significantly the signaling activity of the LRP6 coreceptor. We conclude that the LRP6Δ3 isoform is a novel splice variant, which shows diminished Wnt/β-catenin signaling activity and might have a functional role in individuals with AD.
authors.affiliation: Center for Biomedical Research and FONDAP Center for Genome Regulation, Universidad Andres Bello, Santiago, Chile.
authors.forename: Marcelo A
authors.initials: MA
authors.lastname: Alarcón
authors.forename: Matías A
authors.initials: MA
authors.lastname: Medina
authors.forename: Qubai
authors.initials: Q
authors.lastname: Hu
authors.forename: Miguel E
authors.initials: ME
authors.lastname: Avila
authors.forename: Bernabé I
authors.initials: BI
authors.lastname: Bustos
authors.forename: Eduardo
authors.initials: E
authors.lastname: Pérez-Palma
authors.forename: Alexis
authors.initials: A
authors.lastname: Peralta
authors.forename: Paulina
authors.initials: P
authors.lastname: Salazar
authors.forename: Giorgia D
authors.initials: GD
authors.lastname: Ugarte
authors.forename: Ariel E
authors.initials: AE
authors.lastname: Reyes
authors.forename: George M
authors.initials: GM
authors.lastname: Martin
authors.forename: Carlos
authors.initials: C
authors.lastname: Opazo
authors.forename: Randall T
authors.initials: RT
authors.lastname: Moon
authors.forename: Giancarlo V
authors.initials: GV
authors.lastname: De Ferrari
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D017398:Alternative Splicing / Q000235:genetics; D000544:Alzheimer Disease / Q000175:diagnosis* / Q000235:genetics*; D000818:Animals; D005260:Female; D056726:Genetic Association Studies; D057809:HEK293 Cells; D006801:Humans; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000235:genetics*; D008297:Male; D051379:Mice; D008875:Middle Aged; D020033:Protein Isoforms / Q000235:genetics*; D060449:Wnt Signaling Pathway / Q000235:genetics*
chemical_list: C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D020033:Protein Isoforms