Mutations

PSEN1 V142F

Overview

Pathogenicity: Alzheimer's Disease : Likely Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73640359 G>T
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GTC to TTC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 5

Findings

This mutation was identified in an Iranian family with early onset Alzheimer’s disease (Wang et al., 2018). The mother and four of her six offspring were affected, with ages of onset ranging from 35 to 42 years. Early symptoms included deficits in recent episodic memory and visuospatial perception. These symptoms were followed by deterioration of working memory and executive function, word-finding difficulties, and behavioral changes, including apathy, depression, agitation, aggression, and sleep disorders. Myoclonic jerks were present in all affected individuals at advanced stages of disease. The mother and three of the four affected siblings died within seven years of symptom onset.

DNA samples were available from one affected individual and two of his unaffected siblings. The patient was found to carry a novel mutation in PSEN1 that resulted in a valine-to-phenylalanine substitution at amino acid 142; no other pathogenic mutations were found in APP, PSEN1, or PSEN2 in this individual. The PSEN1 V142F mutation was absent in the two unaffected siblings, in 87 neurologically healthy Iranian controls, and in the gnomAD variant database (gnomAD v2.1.1, May 2021).

Neuropathology

Neuropathological information is not available. However, MRI of one family member during the late stage of disease revealed severe, global cortical atrophy, which was most pronounced in frontal and temporal lobes.

Biological Effect

Several in silico algorithms (MutPred, SNP&Go, SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) predicted this variant is damaging (Wang et al., 2017Xiao et al., 2021).

Valine-142, located in the second transmembrane domain, is conserved across species and in presenilin-2. This residue is located near several other pathogenic PSEN1 mutations aligned along the helical face, supporting the pathogenicity of this mutation (Guerreiro et al., 2010; Wang et al., 2018).

 

Last Updated: 02 Aug 2021

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References

Paper Citations

  1. . Genetic screening in two Iranian families with early-onset Alzheimer's disease identified a novel PSEN1 mutation. Neurobiol Aging. 2018 Feb;62:244.e15-244.e17. Epub 2017 Oct 23 PubMed.
  2. . 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.
  3. . 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.

External Citations

  1. gnomAD v2.1.1

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Genetic screening in two Iranian families with early-onset Alzheimer's disease identified a novel PSEN1 mutation. Neurobiol Aging. 2018 Feb;62:244.e15-244.e17. Epub 2017 Oct 23 PubMed.

Other mutations at this position

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