title: A Novel Alzheimer-Associated SNP in Tmp21 Increases Amyloidogenesis.
abstract: Recent studies suggest that TMP21 is a selective modulator of γ-secretase and its dysregulation affects APP processing, leading to increased Aβ generation. However, the genetic association between Tmp21 and Alzheimer's disease (AD) remains elusive. In this study, we identified that a novel single-nucleotide polymorphism (SNP) rs12435391 (IVS4-28T>C) in intron 4 of Tmp21 was genetically associated with AD. We found that allele C of the SNP rs12435391 did not affect splicing site recognition, but it significantly increased TMP21 gene expression. The stability of Tmp21 pre-mRNA and the transcription of Tmp21 were not affected by allele C of the SNP rs12435391. However, allele C of the SNP rs12435391 significantly increased the splicing efficiency of Tmp21 pre-mRNA, leading to the elevation of mature mRNA. Furthermore, allele C of the SNP rs12435391 significantly reduced C83 level and increased Aβ generation. Taken together, our study suggests that TMP21 is genetically associated with Alzheimer's disease, with the novel Tmp21 SNP as a risk factor for Alzheimer's pathogenesis.
authors.affiliation: Townsend Family Laboratories, Department of Psychiatry, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada.
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Townsend Family Laboratories, Department of Psychiatry, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada.
authors.forename: Yili
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Townsend Family Laboratories, Department of Psychiatry, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada.
authors.forename: Fang
authors.initials: F
authors.lastname: Cai
authors.affiliation: Department of Surgery, The First Affiliated Hospital, Chongqing Medical University, 1 Friendship Road, Yuzhong District, Chongqing, 410006, China.
authors.forename: Shengchun
authors.initials: S
authors.lastname: Liu
authors.affiliation: Townsend Family Laboratories, Department of Psychiatry, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada.
authors.forename: Kelley
authors.initials: K
authors.lastname: Bromley-Brits
authors.affiliation: The State Key Lab of Medical Genetics of China, School of Life Sciences, Central South University, Changsha, 410000, China. xiakun48@163.com.
authors.forename: Kun
authors.initials: K
authors.lastname: Xia
authors.affiliation: Townsend Family Laboratories, Department of Psychiatry, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada. weihong@mail.ubc.ca.
authors.forename: Weihong
authors.initials: W
authors.lastname: Song
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000682:Amyloid / Q000235:genetics* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D029543:Nucleocytoplasmic Transport Proteins; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D008565:Membrane Proteins; D029543:Nucleocytoplasmic Transport Proteins; C484395:TMED10 protein, human
keywords: Alzheimer’s disease; Intron; Single-nucleotide polymorphism; TMP21