Mutations
PSEN2 K306fs
Quick Links
Overview
Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity
Criteria: PM2
Clinical
Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr1:226891308 A>-
Position: (GRCh37/hg19):Chr1:227079009 A>-
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA
Change: Deletion
Expected RNA
Consequence: Deletion
Expected Protein
Consequence: Frame Shift
Codon
Change: AAG.CTG to AGC.TGG
Reference
Isoform: PSEN2 Isoform 1 (448 aa)
Genomic
Region: Exon 10
Findings
This mutation, involving the deletion of a single nucleotide (A) in exon 9, was identified in a Moroccan individual with memory impairment beginning at age 55. He later developed aphasia. The patient's pedigree indicates two affected siblings, but clinical details were not available and segregation with disease could not be assessed (El Kadmiri et al., 2014).
This mutation is absent from the gnomAD variant database (v2.1.1, Nov 2021).
Neuropathology
Unknown. Neuroimaging showed cortical atrophy.
Biological Effect
Unknown. The deletion of a single nucleotide (A) in exon 9 is predicted to result in a frameshift at codon 306.
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.
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.
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
References
Paper Citations
- 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.
Further Reading
No Available Further Reading
Protein Diagram
Primary Papers
- 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.
Alzpedia
Disclaimer: Alzforum does not provide medical advice. The Content is for informational, educational, research and reference purposes only and is not intended to substitute for professional medical advice, diagnosis or treatment. Always seek advice from a qualified physician or health care professional about any medical concern, and do not disregard professional medical advice because of anything you may read on Alzforum.
Comments
The University of Adelaide
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 LardelliRouen University Hospital
Inserm
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-LecruxMake a Comment
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