Identification of a rare presenilin 1 single amino acid deletion mutation (F175del) with unusual amyloid-beta processing effects

Voeglein, Jonathan; Willem, Michael; Trambauer, Johannes; Schönecker, Sonja; Dieterich, Marianne; Biskup, Saskia; Giudici, Camilla; Utz, Kathrin; Oberstein, Timo; Brendel, Matthias; Rominger, Axel; Danek, Adrian; Steiner, Harald; Haass, Christian und Levin, Johannes (2019): Identification of a rare presenilin 1 single amino acid deletion mutation (F175del) with unusual amyloid-beta processing effects. In: Neurobiology of Aging, Bd. 84

Abstract

We report the novel presenilin 1 (PSEN1) single amino acid deletion mutation F175del. Comprehensive clinical work-up, including cerebral MRI, FDG-PET, and CSF analysis, was performed in a male who had developed forgetfulness at the age of 39. Alzheimer's disease dementia was diagnosed according to established criteria. The index patient manifested rapid progressive dementia, seizures, and myoclonus, and a Pisa syndrome as a side effect of donepezil treatment. The PSEN1 mutation F175del was found on genetic testing. It was rendered very likely pathogenic as amyloid-beta (A beta) peptide 42 was elevated in a cell culture model compared to presenilin 1 wild-type controls. An additional, unusual increase in A beta 39 indicates a rarely observed product line deviation in the generation of the shorter A beta species. Our observations extend the range of PSEN1 mutations to be considered in familial dementia. We demonstrate that deletion of a single conserved amino acid, which is very rare compared to missense mutations as the common cause for PSEN1-associated Alzheimer's disease, can lead to an unusual profile of A beta species. (C) 2019 Elsevier Inc. All rights reserved.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin ; Medizin > Munich Cluster for Systems Neurology (SyNergy)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0197-4580
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198