Novel PSEN1 p.Gly417Ala mutation in a Korean patient with early-onset Alzheimer's disease with parkinsonism

Abstract Mutations in presenilin 1 (PSEN1) are the most common cause of autosomal dominant Alzheimer’s disease (AD). Here, we report a 37-year-old male Korean patient carrying a PSEN1 p.Gly417Ala mutation with an exceptionally early and severe presentations, including a wide range of atypical symptoms of rapid cognitive decline with a stooped posture, rigidity, and bradykinesia. Targeted next generation sequencing (NGS) of proband patient revealed a novel nucleotide substitution (c.1250G>C) in exon 12 of PSEN1 gene, altering glycine (Gly) to alanine (Ala) at 417 position. Three-dimensional protein structure prediction revealed that the variant may cause perturbations in the 8th transmembrane region, perturbing its functions from the increased hydrophobicity and size of alanine with decreased flexibility. Since several glycine>alanine substitutions in other PSEN1 transmembrane helices revealed aggressive AD phenotypes, PSEN1 Gly417Ala may share a common pathogenic mechanism.