Mutations

PSEN1 G378fs

Overview

Pathogenicity: Alzheimer's Disease : Unclear Pathogenicity
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73683837 ->G
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Insertion
Codon Change: GGA.GTA to GGG.AGT
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 11

Findings

This mutation, identified in a Moroccan individual, involves the insertion of one nucleotide (G) resulting in a frameshift at codon 378. The mutation carrier presented with symptoms of progressive memory impairment at age 63. Her symptoms, including decreased autonomy and aphasia, were typical of AD. The reported pedigree shows five affected individuals over two generations. Segregation with disease could not be assessed due to lack of DNA from other family members (El Kadmiri et al., 2014).

Neuropathology

Unknown. MRI of the proband showed hippocampal and parahippocampal atrophy (El Kadmiri et al., 2014).

Biological Effect

Unknown. The insertion of one nucleotide in exon 11 is predicted to cause a frameshift.

Comments

  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.

    References:

    . 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).

    References:

    . 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. . 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

  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.

Other mutations at this position

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