Screening and functional validations of APP, PSEN1 and PSEN2 mutations from PUMCH dementia cohort

Abstract

Background: Presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid precursor protein (APP) genes have been verified as causative genes for Alzheimer’s disease (AD). The present study aimed to (1) screen for pathogenic mutations in a large sample size Chinses dementia population (Peking Union Medical College Hospital dementia cohort, PUMCH dementia cohort), (2) determine the functional effect of the identified mutations by in-vitro study. Methods: Next generation sequencing was performed in patients from PUMCH dementia cohort and AD variants interpretation was determined by bioinformatic analysis. AD pathogenicity of the identified variants was determined by detecting the Aβ secretion of transfected HEK293 cells. Results: Among the 1277 participants from PUMCH dementia cohort, 46 patients with causative AD mutations (36 variants) were identified, with frequency of 3.60% (1.25% of APP, 1.25% of PSEN1 and 1.10% of PSEN2). The detected frequency of AD mutations was 6.95% (23/331), 4.24% (32/754), and 11.04% (17/154) in dementia population who have dementia family history, in early-onset dementia population, and in early-onset dementia population who have dementia family history, respectively. Among the 36 identified variants, 6 variants (PSEN1E72K, E363Q and Q223K, PSEN2 N141S, M239T and I368F) were identified to significantly increased the level of Aβ42, Aβ40 or the ratio of Aβ42/Aβ40 compared with wild-type variant by in-vitro study. Conclusion: This study provided the profile of AD mutations of PUMCH dementia cohort and demonstrated the possible AD pathogenicity of 6 variants by in-vitro study.