Mutations

PSEN1 F283L

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease, Corticobasal Syndrome
Reference Assembly: GRCh37 (105)
Position: Chr14:73664818 T>G
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: TTT to TTG
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

This mutation was identified in a screen for APP and PSEN1 mutations in individuals with autosomal-dominant familial AD seen at the Dementia Research Centre in London, U.K. (Scahill et al., 2013; Ryan et al., 2016). The mutation was present in three affected members of a family that included 15 affected individuals with mean age at onset of 46 years. All mutation cases had an amnestic presentation. The mutation was absent from two unaffected family members and 100 healthy controls. 

The mutation was also found in two members of a Canadian family who were diagnosed with having probable corticobasal syndrome (Lam et al., 2017). The age at onset for these patients was 48 and 51 years, with a disease duration of 10 and six years, respectively. Initial symptoms included inattention, dysexecutive syndrome, and depressed mood. In one case, the patient also had memory impairment and personality changes. The mutation was not found in several genetic variant databases, including ExAC, 1000 Genomes, and the Exome Variant Server.

Neuropathology
Neuropathology consistent with AD was reported in two affected individuals from the family with three identified mutation carriers (Ryan et al., 2016). Similarly, the brains of the Canadian mutation carriers revealed typical AD neuropathology, including amyloid angiopathy and neuritic plaques, as well as neurofibrillary tangles in the frontal, temporal, and parietal cortices, despite their corticobasal syndrome diagnoses (Lam et al., 2017). There were no signs of FTLD-tau nor TDP-43 pathology, and only rare α-synuclein- positive Lewy bodies in the amygdala of one case. MRI showed severe parietal, perirolandic, and temporal atrophy with relative sparing of frontal and ipsilateral hippocampal regions. SPECT revealed hypoperfusion of brain regions contralateral to the patients' affected limbs; in one case, specifically temporal and parietal regions. 

Biological Effect
The mutation is predicted to have a damaging effect according to in silico analyses using SIFT, Polyphen, Provean, and Mutation Taster (Ryan et al., 2016Lam et al., 2017). Moreover, it is conserved between species. Ryan and colleagues classified it as definitely pathogenic, as segregation was demonstrated. 

Last Updated: 21 May 2019

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References

Paper Citations

  1. . Genetic Influences on Atrophy Patterns in Familial Alzheimer's Disease: A Comparison of APP and PSEN1 Mutations. J Alzheimers Dis. 2013 Jan 1;35(1):199-212. PubMed.
  2. . Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer's disease: a case series. Lancet Neurol. 2016 Dec;15(13):1326-1335. Epub 2016 Oct 21 PubMed.
  3. . Characterizing familial corticobasal syndrome due to Alzheimer's disease pathology and PSEN1 mutations. Alzheimers Dement. 2016 Oct 12; PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Genetic Influences on Atrophy Patterns in Familial Alzheimer's Disease: A Comparison of APP and PSEN1 Mutations. J Alzheimers Dis. 2013 Jan 1;35(1):199-212. PubMed.
  2. . Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer's disease: a case series. Lancet Neurol. 2016 Dec;15(13):1326-1335. Epub 2016 Oct 21 PubMed.

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