Mutations

PSEN2 K115Efs*

Other Names: K115Efx10

Overview

Pathogenicity: Alzheimer's Disease : Uncertain Significance
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr1:227071608 AG>--
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Deletion
Codon Change: AAG to A--
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 5

Findings

This frameshift mutation in PSEN2 was first detected in a woman referred to the University of Washington in Seattle with early onset Alzheimer’s disease (Jayadev et al., 2010). Starting at age 56, she experienced progressive memory decline and impairments in visual spatial skills and executive function. She had no known family history of neurodegenerative disease, but information regarding her family was limited. She did not carry any known mutations in APP or PSEN1. A subsequent study reported that the proband’s daughter developed subjective mild memory impairment beginning at age 40 (Braggin et al., 2019).

The mutation was found in another woman, also examined at the University of Washington, but who appeared to be unrelated to the initial family (Braggin et al., 2019). In an exome sequence analysis which revealed more than 100 rare variants in the two patients, only the PSEN2 K115Efs* variant was shared. In this new case, the woman presented with poor recall, signs of apraxia, difficulty following commands, perseveration, disinhibition, and a history of persecutory delusions at age 51. By 53, she was unable to stand without assistance, was nearly mute, and was diagnosed with dementia of unclear etiology. Her mother was reportedly diagnosed with AD, but clinical details were unavailable.

The mutation was absent from the gnomAD variant database (v2.1.1, Nov 2021).

Neuropathology

In two cases, severe AD neuropathology was observed, with cerebral amyloid angiopathy in one case, but no microvascular disease (Braggin et al., 2019). Prior to autopsy, in one patient, FDG-PET showed hypometabolism in the parietal and temporal lobes (Jayadev et al., 2010), and in another, MRI revealed moderate to severe cortical atrophy and severe white matter disease.

Biological Effect

The mutation, which was originally reported as K115Efx10, involves the deletion of two nucleotides from exon 5, leading to a frameshift and ultimately to a premature stop codon in exon 6 (Jayadev et al., 2010). A truncated mutant transcript was detected at decreased levels compared to wild‐type, suggesting transcript instability, reduced transcription, or targeting by nonsense-mediated decay (Braggin et al., 2019). Commercial antibodies failed to detect a truncated protein.

In patient fibroblasts, levels of wild‐type PSEN2 transcript and protein were reduced compared to controls, particularly levels of the C-terminus protein fragment (Braggin et al., 2019). In addition, mutant fibroblasts secreted a decreased amount of Aβ40, and levels of Aβ38 and Aβ42 were undetectable.

Interestingly, alternatively spliced transcripts of the mutant allele were detected in brain lysates. Although the splice variants were not unique to the mutant—they were also found in sporadic AD and control brain lysates—in the mutant, they are predicted to generate unique proteins. In one case, a partial intronic retention is expected to cause a 25‐amino acid insertion into the loop between the first and second transmembrane domains. In the other case, the exclusion of exon 6 (PS2V) isoform is predicted to return to the original reading frame after a short frameshift, causing a 48‐amino acid deletion and predicted loss of the entire second transmembrane domain. These altered transcripts are expected to be translated into full‐length proteins due to the loss of the two base pairs of the mutant allele. However, the corresponding protein products were undetectable in brain lysates by Western blot using commercial antibodies. The authors propose this may be due to low percentage or instability of the proteins, additional undetected alternative splicing downstream, or an inability of the antibody to recognize the altered protein products.

Last Updated: 12 Nov 2021

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References

Paper Citations

  1. . Alzheimer's disease phenotypes and genotypes associated with mutations in presenilin 2. Brain. 2010 Apr;133(Pt 4):1143-54. PubMed.
  2. . Alternative splicing in a presenilin 2 variant associated with Alzheimer disease. Ann Clin Transl Neurol. 2019 Apr;6(4):762-777. Epub 2019 Mar 10 PubMed.

Further Reading

Papers

  1. . Alzheimer's disease-related peptide PS2V plays ancient, conserved roles in suppression of the unfolded protein response under hypoxia and stimulation of γ-secretase activity. Hum Mol Genet. 2015 Jul 1;24(13):3662-78. Epub 2015 Mar 26 PubMed.
  2. . Accelerated brain aging towards transcriptional inversion in a zebrafish model of the K115fs mutation of human PSEN2. PLoS One. 2020;15(1):e0227258. Epub 2020 Jan 24 PubMed.
  3. . A novel presenilin-2 splice variant in human Alzheimer's disease brain tissue. J Neurochem. 1999 Jun;72(6):2498-505. PubMed.

Protein Diagram

Primary Papers

  1. . Alzheimer's disease phenotypes and genotypes associated with mutations in presenilin 2. Brain. 2010 Apr;133(Pt 4):1143-54. PubMed.

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