Mutations

PSEN1 F175del

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Myoclonic seizure, Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73653605 TTC>---
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Deletion
Codon Change: TTC to ---
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 6

Findings

This mutation was identified in a man diagnosed with AD who developed alterations in memory and personality at age 39 (Vöglein et al., 2019). He experienced rapid progressive dementia, seizures, and myoclonus. The patient’s mother developed dementia in her early 30s and died at 36, and his grandmother was diagnosed with AD before her death at age 50, suggesting autosomal dominant inheritance.

Neuropathology
Although neuropathological data are unavailable, MRI showed atrophy of the medial temporal lobe and FDG-PET revealed alterations typical of AD. Metabolism was markedly reduced in the precuneus/posterior cingulate and parietotemporal cortex, while perirolandic metabolism remained intact. Moreover, cerebrospinal fluid levels of Aβ42 were decreased, while those of total tau and phosphorylated tau were increased, as typically seen in AD patients.

Biological Effect
Cultured human embryonic kidney cells expressing APP with the Swedish mutation (APPswe) and the PSEN1 F175del mutation secreted more Aβ42 and less Aβ40, measured as a fraction of total Aβ, than cells expressing APPswe and wildtype PSEN1.  In addition, denaturing gel electrophoresis of conditioned media revealed increased levels of Aβ39, an alternative fragment generated from Aβ42. This observation was confirmed by MALDI-TOF mass spectrometry. Endoproteolysis of PSEN1 appeared unaffected. The authors considered the mutation probably pathogenic, in accordance with the Guerreiro et al. 2010 guidelines.

Last Updated: 13 Nov 2019

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References

Paper Citations

  1. . Identification of a rare presenilin 1 single amino acid deletion mutation (F175del) with unusual amyloid-β processing effects. Neurobiol Aging. 2019 Dec;84:241.e5-241.e11. Epub 2019 Sep 20 PubMed.
  2. . Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP. Neurobiol Aging. 2010 May;31(5):725-31. Epub 2008 Jul 30 PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Identification of a rare presenilin 1 single amino acid deletion mutation (F175del) with unusual amyloid-β processing effects. Neurobiol Aging. 2019 Dec;84:241.e5-241.e11. Epub 2019 Sep 20 PubMed.

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