Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Spastic Paraparesis, Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73673096 A>C
dbSNP ID: rs63750298
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: ACA to CCA
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 9

Findings

This mutation was identified in a French individual who was referred to a neurologist at age 33 for progressive motor impairment, including a spastic gait. Ten years later, he required a wheelchair and had severe dysarthria (difficulty speaking due to impairment of speech producing muscles). He had also developed dementia with prominent frontal lobe dysfunction. Segregation with disease could not be determined due to lack of DNA from relatives (Dumanchin et al., 2006).

Neuropathology

Unknown, but MRI showed marked diffuse atrophy and a signal in the right temporal lobe, compatible with previous bleeding (Dumanchin et al., 2006).

Biological Effect

When expressed in HEK293 cells, this mutation increased Aβ40 and Aβ42 measured in the conditioned media. Although the concentrations of both peptides increased, the increase was greater for Aβ42 and the overall ratio of Aβ42/Aβ40 was significantly altered compared to cells expressing wild-type PSEN1 (Dumanchin et al., 2006). However, in an in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate, it generated dramatically less Aβ42 than the wild-type protein and abolished Aβ40 production (Sun et al., 2017).

This point mutation has also been shown to affect exon 9 splicing, leading to the exclusion of exon 9 in about 5 percent of transcripts (Dumanchin et al., 2006).

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References

Paper Citations

1. Dumanchin C, Tournier I, Martin C, Didic M, Belliard S, Carlander B, Rouhart F, Duyckaerts C, Pellissier JF, Latouche JB, Hannequin D, Frebourg T, Tosi M, Campion D. Biological effects of four PSEN1 gene mutations causing Alzheimer disease with spastic paraparesis and cotton wool plaques. Hum Mutat. 2006 Oct;27(10):1063. PubMed.
2. Sun L, Zhou R, Yang G, Shi Y. Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase. Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E476-E485. Epub 2016 Dec 5 PubMed.

Further Reading

No Available Further Reading