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A Possible Pathogenic PSEN2 Gly56Ser Mutation in a Korean Patient with Early-Onset Alzheimer's Disease.

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  • Additional Information
    • Source:
      Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE
    • Publication Information:
      Original Publication: Basel, Switzerland : MDPI, [2000-
    • Subject Terms:
      Alzheimer Disease*/diagnosis ; Alzheimer Disease*/genetics; Amyloid beta-Peptides/genetics ; Amyloid beta-Protein Precursor/genetics ; Female ; Humans ; Middle Aged ; Mutation ; Presenilin-1/genetics ; Presenilin-2/genetics ; Republic of Korea ; Serine/genetics
    • Abstract:
      Early-onset Alzheimer’s disease (EOAD) is characterized by the presence of neurological symptoms in patients with Alzheimer’s disease (AD) before 65 years of age. Mutations in pathological genes, including amyloid protein precursor (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2), were associated with EOAD. Seventy-six mutations in PSEN2 have been found around the world, which could affect the activity of γ-secretase in amyloid beta processing. Here, a heterozygous PSEN2 point mutation from G to A nucleotide change at position 166 (codon 56; c.166G>A, Gly56Ser) was identified in a 64-year-old Korean female with AD with progressive cognitive memory impairment for the 4 years prior to the hospital visit. Hippocampal atrophy was observed from magnetic resonance imaging-based neuroimaging analyses. Temporal and parietal cortex hypometabolisms were identified using fluorodeoxyglucose positron emission tomography. This mutation was at the N-terminal portion of the presenilin 2 protein on the cytosolic side. Therefore, the serine substitution may have promoted AD pathogenesis by perturbing to the mutation region through altered phosphorylation of presenilin. In silico analysis revealed that the mutation altered protein bulkiness with increased hydrophilicity and reduced flexibility of the mutated region of the protein. Structural changes were likely caused by intramolecular interactions between serine and other residues, which may have affected APP processing. The functional study will clarify the pathogenicity of the mutation in the future.
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    • Grant Information:
      2021R1A6A1A03038996 National Research Foundation of Korea; VHSM21023 VHS Medical Center research grant
    • Contributed Indexing:
      Keywords: Alzheimer’s disease; PSEN2 Gly56Ser mutation; hippocampal atrophy; mutation; phosphorylation; presenilin 2
    • Accession Number:
      0 (Amyloid beta-Peptides)
      0 (Amyloid beta-Protein Precursor)
      0 (PSEN2 protein, human)
      0 (Presenilin-1)
      0 (Presenilin-2)
      452VLY9402 (Serine)
    • Publication Date:
      Date Created: 20220325 Date Completed: 20220408 Latest Revision: 20230308
    • Publication Date:
      20250114
    • Accession Number:
      PMC8953053
    • Accession Number:
      10.3390/ijms23062967
    • Accession Number:
      35328387