Pathogenicity: Alzheimer's Disease : Pathogenic, Spastic Paraparesis : Pathogenic
Clinical Phenotype: Spastic Paraparesis, Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73664802 G>A
dbSNP ID: rs63749891
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: AGA to AAA
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 8


This mutation was found in three individuals in the same family who developed a diverse set of symptoms in their 40s (Assini et al., 2003). One woman initially presented with progressive paraperesis, developing dementia five years later. Her daughter, on the other hand, suffered from delusional thinking followed by progressive cognitive decline, without apparent motor symptoms. Moreover, her brother was first diagnosed with spastic paraperesis and 12 years later developed difficulty recalling words, with no other apparent cognitive impairment. The mutation was absent from 150 healthy controls. 


Although neuropathology data are unavailable, the brother was reported as having normal MRI and CT scans.

Biological Effect

Increased Aβ42 was detected in the conditioned medium of fibroblasts from the two siblings, while Aβ40 levels were similar to controls (Assini et al., 2003). However, another study reported reduced Aβ42 and Aβ40 production using purified proteins to test the ability of the mutant to cleave the APP-C99 substrate in vitro (Sun et al., 2017). In both studies, the Aβ42/Aβ40 ratio was increased relative to controls.

As revealed by a cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment, R278 appears to play a key role in stabilizing the hybrid β-sheet that forms between PSEN1 and APP in preparation for cleavage (Zhou et al., 2019; Jan 2019 news).

Last Updated: 06 Aug 2019


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News Citations

  1. CryoEM γ-Secretase Structures Nail APP, Notch Binding

Paper Citations

  1. . Pure spastic paraparesis associated with a novel presenilin 1 R278K mutation. Neurology. 2003 Jan 14;60(1):150. PubMed.
  2. . 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.
  3. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.

Further Reading

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Protein Diagram

Primary Papers

  1. . Pure spastic paraparesis associated with a novel presenilin 1 R278K mutation. Neurology. 2003 Jan 14;60(1):150. PubMed.

Other mutations at this position


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