Mutations

PSEN1 A434T

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Parkinsonism, Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73685893 G>A
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GCT to ACT
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 12

Findings

This mutation was detected in a Chinese family with a history of Alzheimer's disease. The proband was initially misdiagnosed with schizophrenia due to presenting symptoms of hallucinations and delusions at age 35. Progressive memory deficits became apparent later and she met criteria for AD. Her mother had been diagnosed with AD at the age of 55 (symptom onset at age 50). She had pronounced memory impairment but other cognitive domains were preserved. The mutation appears to segregate with disease in this family; it was present in both the proband and her affected mother (Jiao et al., 2014).

This mutation was also identified in a retrospective analysis of genotypic and phenotypic data from 213 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). It was found in a patient carrying an additional, novel presenilin 1 variant, PSEN1 T291A. The patient had AD pathology with cotton wool plaques, diffuse amyloid deposits, and severe amyloid angiopathy.

The mutation has also been linked to parkinsonism (Jo et al., 2019). A 43-year-old mutation carrier presented with dementia, as well as right-side dominant parkinsonism which progressed to bilateral parkinsonism. The phenotype was markedly relieved by L-dopa.

Neuropathology

Neuropathological data are unavailable, however, florbetaben-PET imaging of the patient with parkinsonism revealed amyloid accumulation in the cortex, with minimal accumulation in the striatum (Jo et al., 2019). FP-CIT-PET to detect dopamine transporters revealed decreased levels in the contralateral striatum of this patient's affected side.

Biological Effect

The biological effect of this mutation is unknown, but it was predicted damaging by in silico analysis with SIFT software. Jiao et al., 2014 classified it as definitely pathogenic according to the algorithm proposed in Guerreiro et al., 2010. Moreover, A434 has been shown to directly interact with APP, forming part of the PAL motif implicated in the recognition of APP by γ-secretase (Sato et al., 2008; Zhou et al., 2019; Jan 2019 news).

Last Updated: 12 Aug 2019

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References

Mutations Citations

  1. PSEN1 T291A

News Citations

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

Paper Citations

  1. . Mutational analysis in early-onset familial Alzheimer's disease in Mainland China. Neurobiol Aging. 2014 Aug;35(8):1957.e1-6. Epub 2014 Feb 20 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. . Dopa Responsive Parkinsonism in an Early Onset Alzheimer's Disease Patient with a Presenilin 1 Mutation (A434T). J Alzheimers Dis. 2019;71(1):7-13. PubMed.
  4. . 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.
  5. . The C-terminal PAL motif and transmembrane domain 9 of presenilin 1 are involved in the formation of the catalytic pore of the gamma-secretase. J Neurosci. 2008 Jun 11;28(24):6264-71. PubMed.
  6. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Mutational analysis in early-onset familial Alzheimer's disease in Mainland China. Neurobiol Aging. 2014 Aug;35(8):1957.e1-6. Epub 2014 Feb 20 PubMed.

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