The curious case of a heterozygous loss-of-function <i>PSEN1</i> variant associated with early-onset Alzheimer's disease.

ABSTRACT:

Background

Over 300 mutations in PSEN1 have been identified as causes of early-onset Alzheimer's disease (EOAD). While these include missense mutations and a few insertions, deletions, or duplications, none result in open reading frame shifts, and all alter γ-secretase function to increase the long/short Aβ ratio.

Methods

We identified a novel heterozygous PSEN1 nonsense variant, c.325A > T, in a patient and his father, both presenting with EOAD, resulting in the substitution of lysine 109 with a premature stop codon at position (p.K109*). This produces a truncated 109 amino acid (aa) N-terminal PSEN1 fragment. Functional characterization was performed using overexpression models and a heterozygous mouse model (Psen1^K109*/+).

Results

In overex

SUBMITTER: Sanjuan-Ruiz I 

PROVIDER: S-EPMC12537781 | biostudies-literature | 2025

REPOSITORIES: biostudies-literature