PSEN2 E126fs


Pathogenicity: Alzheimer's Disease : Not Classified
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr1:227073260 ->A
Coding/Non-Coding: Coding
Mutation Type: Insertion
Codon Change: GAG.GAC to GAA.GGA
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 6


This mutation, involving the insertion of a single nucleotide (A) in exon 5 and resulting in a frameshift after codon 126, was identified in a Moroccan individual with memory impairment beginning at age 60. He later developed primary progressive aphasia. His mother was thought to have had Alzheimer's disease, but clinical details were not available and segregation with disease could not be assessed (El Kadmiri et al., 2014).

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


Unknown. Neuroimaging showed hippocampal and parahippocampal atrophy. 

Biological Effect

Mouse neuroblastoma cells expressing this variant secreted dramatically less Aβ42 and Aβ40 than cells expressing wild-type PSEN2, and the Aβ42/Aβ40 ratio was moderately reduced (Hsu et al., 2020). The authors classified it as a "risk factor," but also noted the reduction in Aβ production could confer resilience to AD.

Last Updated: 03 Nov 2021


  1. I must admit to being somewhat skeptical about the results presented in this paper and in a sister paper on novel mutations in APP. It seems remarkable (and highly improbable) that the researchers would discover numerous novel frameshift familial AD (FAD) mutations truncating the open reading frames of PSEN1 and PSEN2 among a small number of families when the only such mutation that I know of previously published is K115Efx10 in PSEN2 (Jayadev et al., 2010) among the 180-plus FAD mutations known in these two genes (the rest of which preserve the genes' open reading frames). The sequence data presented is not especially convincing.


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

    View all comments by Michael Lardelli
  2. We have concerns about the validity of the frameshift mutations in PSEN1 and PSEN2 reported here. Beyond the fact that there is no genetic evidence in the literature that PSEN1 or PSEN2 haploinsufficiency causes Alzheimer’s disease, we are not convinced by the DNA sequencing electropherogram images in Figures 1 and 2. From a technical point of view, a weak signal and/or background noise may lead to the false detection of single base pair insertions or deletions. Hence, the existence of the mutations in these patients appears to be uncertain. Likewise, we have similar concerns about a related paper reporting frameshift mutations in APP (El Kadmiri et al., 2014).


    . Novel mutations in the amyloid precursor protein gene within Moroccan patients with Alzheimer's disease. J Mol Neurosci. 2014 Jun;53(2):189-95. Epub 2014 Mar 14 PubMed.

    View all comments by Anne Rovelet-Lecrux

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Paper Citations

  1. . Novel presenilin mutations within Moroccan patients with Early-Onset Alzheimer's Disease. Neuroscience. 2014 Jun 6;269:215-22. Epub 2014 Apr 4 PubMed.
  2. . Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2. Neurobiol Dis. 2020 Jun;139:104817. Epub 2020 Feb 19 PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Novel presenilin mutations within Moroccan patients with Early-Onset Alzheimer's Disease. Neuroscience. 2014 Jun 6;269:215-22. Epub 2014 Apr 4 PubMed.

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