Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PM2, BS3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr1:226885559_226885560 ->A
Position: (GRCh37/hg19):Chr1:227073260_227073261 ->A
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Insertion
Expected RNA Consequence: Insertion
Expected Protein Consequence: Frame Shift
Codon Change: GAG.GAC to GAA.GGA
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 6

Findings

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).

Neuropathology

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.

Pathogenicity

Alzheimer's Disease : Not Classified*

*This variant fulfilled some ACMG-AMP criteria, but it was not classified by Alzforum, because data for either a pathogenic or benign classification are lacking: only one affected carrier has been reported without co-segregation data, and the variant is absent—or very rare—in the gnomAD database.

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

Comments

1. • Michael Lardelli
     The University of Adelaide
   • Posted: 16 Apr 2014
   • Paper: Novel presenilin mutations within Moroccan patients with Early-Onset Alzheimer's Disease.

   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.

   References:

   Jayadev S, Leverenz JB, Steinbart E, Stahl J, Klunk W, Yu CE, Bird TD. 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. • Gael Nicolas
     Rouen University Hospital
   • Anne Rovelet-Lecrux
     Inserm
   • Posted: 10 Jul 2017
   • Paper: Novel presenilin mutations within Moroccan patients with Early-Onset Alzheimer's Disease.

   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).

   References:

   El Kadmiri N, Zaid N, Hachem A, Zaid Y, Dubé MP, Hamzi K, El Moutawakil B, Slassi I, Nadifi S. 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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References

Paper Citations

1. El Kadmiri N, Zaid N, Zaid Y, Tadevosyan A, Hachem A, Dubé MP, Hamzi K, El Moutawakil B, Slassi I, Nadifi S. 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. Hsu S, Pimenova AA, Hayes K, Villa JA, Rosene MJ, Jere M, Goate AM, Karch CM. 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