Mutations

PSEN1 A434T

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease, Parkinsonism
Position: (GRCh38/hg38):Chr14:73219185 G>A
Position: (GRCh37/hg19):Chr14:73685893 G>A
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: 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 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 of uncertain significance, PSEN1 T291A. This individual had neuropathology consistent with AD (see below).

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.

This variant was absent from the gnomAD variant database (gnomAD v2.1.1, August 2021).

Neuropathology

The individual carrying both the A434T and  T291A variants had AD pathology with cotton wool plaques, diffuse amyloid deposits, and severe amyloid angiopathy. Moreover, 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). Moreover, several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) predicted this variant is damaging (Xiao et al., 2021).

Pathogenicity

Alzheimer's Disease : Pathogenic

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

PM1-S

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. A434T: Variant is in a mutational hot spot and cryo-EM data suggest residue is of functional importance.

PM2-M

Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. *Alzforum uses the gnomAD variant database.

PM5-M

Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.

PP2-P

Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.

PP3-P

Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). *In most cases, Alzforum applies this criterion when the variant’s PHRED-scaled CADD score is greater than or equal to 20.

Pathogenic (PS, PM, PP) Benign (BA, BS, BP)
Criteria Weighting Strong (-S) Moderate (-M) Supporting (-P) Supporting (-P) Strong (-S) Strongest (BA)

Last Updated: 22 Feb 2022

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References

Mutations Citations

  1. PSEN1 T291A

News Citations

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

Paper Citations

  1. Jiao B, Tang B, Liu X, Xu J, Wang Y, Zhou L, Zhang F, Yan X, Zhou Y, Shen L. 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. Ryan NS, Nicholas JM, Weston PS, Liang Y, Lashley T, Guerreiro R, Adamson G, Kenny J, Beck J, Chavez-Gutierrez L, de Strooper B, Revesz T, Holton J, Mead S, Rossor MN, Fox NC. 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. Jo H, Kim M, Park S, Park JE, Cho SH, Kim SJ, Jang H, Jung YH, Kim J, Na DL, Seo SW, Cho JW, Kim HJ. 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. Guerreiro RJ, Baquero M, Blesa R, Boada M, Brás JM, Bullido MJ, Calado A, Crook R, Ferreira C, Frank A, Gómez-Isla T, Hernández I, Lleó A, Machado A, Martínez-Lage P, Masdeu J, Molina-Porcel L, Molinuevo JL, Pastor P, Pérez-Tur J, Relvas R, Oliveira CR, Ribeiro MH, Rogaeva E, Sa A, Samaranch L, Sánchez-Valle R, Santana I, Tàrraga L, Valdivieso F, Singleton A, Hardy J, Clarimón J. 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. Sato C, Takagi S, Tomita T, Iwatsubo T. 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. Zhou R, Yang G, Guo X, Zhou Q, Lei J, Shi Y. Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
  7. Xiao X, Liu H, Liu X, Zhang W, Zhang S, Jiao B. APP, PSEN1, and PSEN2 Variants in Alzheimer's Disease: Systematic Re-evaluation According to ACMG Guidelines. Front Aging Neurosci. 2021;13:695808. Epub 2021 Jun 18 PubMed.

External Citations

  1. gnomAD v2.1.1

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. Jiao B, Tang B, Liu X, Xu J, Wang Y, Zhou L, Zhang F, Yan X, Zhou Y, Shen L. 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.

Other mutations at this position

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