The identification of PSEN1 p.Tyr159Ser mutation in a non-canonic early-onset Alzheimer's disease family

More than 300 missense mutations in PSEN1 gene have been correlated to the early-onset Alzheimer's disease (EOAD), but given the high diversity of PS1 (the PSEN1 gene product) substrates and the involvement of PS1 in multiple biological functions, different mutants may represent different EOAD etiologies, and how each mutant contributes to the EOAD remains to be further investigated. Here we report the identification of a novel PSEN1 p.Tyr159Ser in a family with multiple EOAD cases. The mutant PS1 protein (PS1Y159S) was analyzed for its activity in producing amyloid-β (Aβ) and for the efficiency in maturation in vitro. We also screened other mutations and SNPs that may modify the effect of PSEN1 p.Tyr159Ser on AD pathogenesis. The blood samples of the family were collected for whole-exome gene sequencing and analysis. The identified mutant PS1 and several other PS1 mutants were co-expressed with the APP Swedish mutant to compare the effects on APP processing and PS1 maturation.1. The proband and her siblings over 50 years old showed typical AD or MCI symptoms. Exon sequencing identified the p.Tyr159Ser mutation in the PSEN1 gene. As not until the age of 78 did the proband's mother who carried this mutation displayed the symptoms of uncharacterized neuropsychiatry instead of AD, but all the mutation bearing lower generation developed AD or MCI after the age of 50, we also analyzed mutations/SNPs that are different between the mother and the lower generation. By in vitro assays, we found that the Y159S substitution strongly increased Aβ42/Aβ40 ratio and significantly affected PS1 maturation. The newly discovered PSEN1 p.Tyr159Ser is an AD-causing mutation, yet, the carriers are not obligated AD patients. Mutations/SNPs in other gene may modify the effects of this mutation, and the identification of these mutations/SNPs may facilitate the discovery of AD-preventing mechanisms and methods. [Display omitted] •The PSEN1 gene mutations are the most common disease-causing gene of familial Alzheimer's disease.•The PS1 Y159S substitution due to the p.Tyr159Ser mutation in PSEN1 alters the Aβ 42/ Aβ 40 ratio in APP metabolism.•Clinical characteristics of carriers of the mutation within the same family can be different and atypical.•The proband’s mother carrying this mutation showed psychotic symptoms but not demetia at the age of 78.•The pathogenic effects of PSEN1 mutations could be modified by special gene SNP polymorphic interactions.