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Alzheimer Disease Pathology-Associated Polymorphism in a Complex Variable Number of Tandem Repeat Region Within the MUC6 Gene, Near the AP2A2 Gene.
Monday,2020-08-24 18:18 America/Los_Angeles — ecterry
| Title | Alzheimer Disease Pathology-Associated Polymorphism in a Complex Variable Number of Tandem Repeat Region Within the MUC6 Gene, Near the AP2A2 Gene. |
| Publication Type | Journal Article |
| Year of Publication | 2020 |
| Authors | Katsumata, Y, Fardo, DW, Bachstetter, AD, Artiushin, SC, Wang, W-X, Wei, A, Brzezinski, LJ, Nelson, BG, Huang, Q, Abner, EL, Anderson, S, Patel, I, Shaw, BC, Price, DA, Niedowicz, DM, Wilcock, DW, Jicha, GA, Neltner, JH, Van Eldik, LJ, Estus, S, Nelson, PT |
| Journal | J Neuropathol Exp Neurol |
| Volume | 79 |
| Issue | 1 |
| Pagination | 3-21 |
| Date Published | 2020 01 01 |
| ISSN | 1554-6578 |
| Keywords | Adaptor Protein Complex 2, Adaptor Protein Complex alpha Subunits, Aged, Aged, 80 and over, Alzheimer Disease, Autopsy, Cohort Studies, Female, Genome-Wide Association Study, Genotype, Humans, Male, Minisatellite Repeats, Mucin-6, Neurofibrillary Tangles, Polymorphism, Genetic, Polymorphism, Single Nucleotide, TDP-43 Proteinopathies |
| Abstract | <p>We found evidence of late-onset Alzheimer disease (LOAD)-associated genetic polymorphism within an exon of Mucin 6 (MUC6) and immediately downstream from another gene: Adaptor Related Protein Complex 2 Subunit Alpha 2 (AP2A2). PCR analyses on genomic DNA samples confirmed that the size of the MUC6 variable number tandem repeat (VNTR) region was highly polymorphic. In a cohort of autopsied subjects with quantitative digital pathology data (n = 119), the size of the polymorphic region was associated with the severity of pTau pathology in neocortex. In a separate replication cohort of autopsied subjects (n = 173), more pTau pathology was again observed in subjects with longer VNTR regions (p = 0.031). Unlike MUC6, AP2A2 is highly expressed in human brain. AP2A2 expression was lower in a subset analysis of brain samples from persons with longer versus shorter VNTR regions (p = 0.014 normalizing with AP2B1 expression). Double-label immunofluorescence studies showed that AP2A2 protein often colocalized with neurofibrillary tangles in LOAD but was not colocalized with pTau proteinopathy in progressive supranuclear palsy, or with TDP-43 proteinopathy. In summary, polymorphism in a repeat-rich region near AP2A2 was associated with neocortical pTau proteinopathy (because of the unique repeats, prior genome-wide association studies were probably unable to detect this association), and AP2A2 was often colocalized with neurofibrillary tangles in LOAD.</p> |
| DOI | 10.1093/jnen/nlz116 |
| Alternate Journal | J. Neuropathol. Exp. Neurol. |
| PubMed ID | 31748784 |
| Grant List | R56 AG057191 / AG / NIA NIH HHS / United States U01 AG032984 / AG / NIA NIH HHS / United States R01 AG033193 / AG / NIA NIH HHS / United States UF1 AG047133 / AG / NIA NIH HHS / United States U01 AG049505 / AG / NIA NIH HHS / United States U01 AG049506 / AG / NIA NIH HHS / United States U01 AG049507 / AG / NIA NIH HHS / United States U01 AG049508 / AG / NIA NIH HHS / United States U01 AG052411 / AG / NIA NIH HHS / United States U01 AG052410 / AG / NIA NIH HHS / United States U01 AG052409 / AG / NIA NIH HHS / United States U54 AG052427 / AG / NIA NIH HHS / United States RC2 HL102419 / HL / NHLBI NIH HHS / United States R01 AG033193 / AG / NIA NIH HHS / United States HHSN268201100005C / HL / NHLBI NIH HHS / United States HHSN268201100006C / HL / NHLBI NIH HHS / United States HHSN268201100007C / HL / NHLBI NIH HHS / United States HHSN268201100008C / HL / NHLBI NIH HHS / United States HHSN268201100009C / HL / NHLBI NIH HHS / United States HHSN268201100010C / HL / NHLBI NIH HHS / United States HHSN268201100011C / HL / NHLBI NIH HHS / United States HHSN268201100012C / HL / NHLBI NIH HHS / United States HHSN268201200036C / HL / NHLBI NIH HHS / United States N01HC55222 / HL / NHLBI NIH HHS / United States N01HC85079 / HL / NHLBI NIH HHS / United States N01HC85080 / HL / NHLBI NIH HHS / United States N01HC85081 / HL / NHLBI NIH HHS / United States N01HC85082 / HL / NHLBI NIH HHS / United States N01HC85083 / HL / NHLBI NIH HHS / United States N01HC85086 / HL / NHLBI NIH HHS / United States U01 HL080295 / HL / NHLBI NIH HHS / United States U01 HL130114 / HL / NHLBI NIH HHS / United States R01 AG023629 / AG / NIA NIH HHS / United States R01 AG020098 / AG / NIA NIH HHS / United States N01HC25195 / HL / NHLBI NIH HHS / United States HHSN268201500001I / HL / NHLBI NIH HHS / United States R01 AG054076 / AG / NIA NIH HHS / United States R01 AG049607 / AG / NIA NIH HHS / United States R01 AG033040 / AG / NIA NIH HHS / United States R01 NS017950 / NS / NINDS NIH HHS / United States U54 HG003273 / HG / NHGRI NIH HHS / United States U54 HG003067 / HG / NHGRI NIH HHS / United States U01 AG057659 / AG / NIA NIH HHS / United States U54 HG003079 / HG / NHGRI NIH HHS / United States U24 AG021886 / AG / NIA NIH HHS / United States U01 AG016976 / AG / NIA NIH HHS / United States U24 AG041689 / AG / NIA NIH HHS / United States |
ePub date:
20/01