A novel presenilin 1 mutation associated with Pick's disease but not β‐amyloid plaques

TLDR

Familial frontotemporal dementia with tauopathy is usually caused by MAPT mutations, but rare cases lacking MAPT implicate other genetic defects, including recently reported PS1 mutations. The study reports a novel PS1 mutation in a patient with Pick‑type tauopathy lacking extracellular β‑amyloid deposits. The Gly183Val mutation is predicted to substitute glycine with valine at codon 183 and disrupt the splice signal at the sixth exon–intron junction. Clinical‑genetic analysis revealed a family history of FTD‑like dementia, phenotypic heterogeneity, and positioned PS1 as a candidate gene for Pick‑type tauopathy without MAPT mutations.

Abstract

Abstract Familial forms of frontotemporal dementia (FTD) with tauopathy are mostly caused by mutations in the gene encoding the microtubule‐associated protein tau (MAPT). However, rare forms of familial tauopathy without MAPT mutations have been reported, suggesting other tauopathy‐related genetic defects. Interestingly, two presenilin 1 (PS1) mutations (Leu113Pro and insArg352) recently have been associated with familial FTD albeit without neuropathological confirmation. We report here a novel PS1 mutation in a patient with Pick‐type tauopathy in the absence of extracellular β‐amyloid deposits. The mutation is predicted to substitute Gly→Val at codon position 183 (Gly183Val) and to affect the splice signal at the junction of the sixth exon and intron. Further clinical‐genetic investigation showed a positive family history of FTD‐like dementia and suggested that Gly183Val is associated with a phenotypically heterogeneous neurodegenerative disorder. Our results suggest PS1 as a candidate gene for Pick‐type tauopathy without MAPT mutations.