Mutations

PSEN1 S132A

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic, Dementia with Lewy Bodies : Pathogenic
Clinical Phenotype: Dementia with Lewy Bodies, Myoclonus
Reference Assembly: GRCh37 (105)
Position: Chr14:73640329 T>G
dbSNP ID: rs200937800
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: TCA to GCA
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 5

Findings

This mutation was identified in a retrospective analysis of genotypic and phenotypic data from individuals with autosomal-dominant familial AD due to APP or PSEN1 mutations seen at the Dementia Research Centre in London, U.K (Ryan et al., 2016).  The carrier of this mutation presented with a dementia with Lewy bodies phenotype. He developed memory impairment at age 59 with early symptoms of visual dysfunction and difficulty learning new tasks. He subsequently developed visual hallucinations, paranoia, and dyspraxia, He also developed myoclonic jerks, bradykinesia, and increased limb tone throughout. His family included three affected individuals with ages of disease onset ranging from 58-60 years.

In addition to the S132A mutation, the patient also had an intronic variant in the MAPT gene (NM_005910・5: rs11872014), but it was considered unlikely to be pathogenic given its presence in an elderly healthy control. Also, the MAPT variant has been described hundreds of times in the Exome Aggregate Consortium (ExAC) dataset. 

The S132A mutation was also found in two individuals in a screen of 3241 U.K. patients with dementia; one case diagnosed with early onset AD and the other with early onset frontotemporal dementia (Koriath et al., 2018). 

The mutation was found in one individual of European ancestry in the ExAC dataset, but was absent from 100 healthy, white controls (Ryan et al., 2016). It was classified as likely deleterious and most likely fully penetrant, with an allele count of one and a frequency of 0.000004 in the gnomAD variant database (Koriath et al., 2018). 

Neuropathology

The proband had AD pathology with severe neocortical Lewy body disease identified post mortem at 70 years of age. At 64, an MRI scan revealed widespread atrophy.

Biological Effect

The affected amino acid is conserved between PSENs and located close to the second transmembrane domain. The variant was predicted to be probably damaging by Polyphen and “neutral” by Provean. Ryan and colleagues classified it as possibly pathogenic.

Last Updated: 30 Jul 2019

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References

Paper Citations

  1. . 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.
  2. . Predictors for a dementia gene mutation based on gene-panel next-generation sequencing of a large dementia referral series. Mol Psychiatry. 2018 Oct 2; PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . 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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