A Rare Variation in the 3' Untranslated Region of the Presenilin 2 Gene Is Linked to Alzheimer's Disease.

Rare variations in coding regions may alter the amino acid sequence and function of presenilins (PSENs), which results in the dysfunction of gamma-secretase, in turn contributing to the development of familial Alzheimer's disease (AD). However, whether rare variations in the 3' untranslated region (UTR) may change the expression level of PSEN2 leading to AD remains unclear. In a familial AD pedigree, DNA samples of the patients were screened for APP, PSEN1, and PSEN2 gene mutations using Sanger sequencing. Allele A of rs537889666, a rare variation located in the 3' UTR of PSEN2, was found in all AD patients, but not in the healthy control in the family. Cosegregation analysis (n = 5) revealed that allele A of rs537889666 may be a pathogenic rare variation. The dual-luciferase assay revealed that allele A suppressed the combination of miR-183-5p and the 3' UTR of PSEN2, which may block the miR-183-5p-mediated suppression of PSEN2 expression. Further study showed an elevated ratio of Aβ42/40 under overexpressed PSEN2 conditions. Measurements of the cerebrospinal fluid showed that PSEN2 levels were increased in both sporadic and AD in this family, suggesting that elevated PSEN2 was associated with the disease. In addition, the miR-183-5p inhibitor or mimic can increase or decrease Aβ42/40 ratios. In conclusion, the results indicate that allele A of rs537889666 upregulated PSEN2 levels, increasing the Aβ42/40 ratio and contributing to AD development.