Mutations

PSEN1 c.869-22_869-23ins18 (ΔE9)

Other Names: ΔE9, Δ9, deltaE9

Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM4, BP4
Clinical Phenotype: Alzheimer's Disease, Spastic Paraparesis
Position: (GRCh38/hg38):Chr14:73206363_73206364 ->TGGAATTTTGTGCTGTTG
Position: (GRCh37/hg19):Chr14:73673071_73673072 ->TGGAATTTTGTGCTGTTG
dbSNP ID: NA
Coding/Non-Coding: Both
DNA Change: Insertion
Expected RNA Consequence: Splicing Alteration
Expected Protein Consequence: Deletion
Genomic Region: Intron 8, Exon 9

Findings

This mutation involves the insertion of 18 nucleotides in intron 8 (c.869-22_869-23insTGGAATTTTGTGCTGTTG) and results in the in-frame skipping of exon 9. It is one of several mutations in PSEN1 that are notable for exclusion of exon 9, which are variously referred to as ΔE9, Δ9, delE9, or deltaE9. This particular mutation was identified in a French patient whose family had a history of dementia (three affected family members in two generations). Onset ranged from 42 to 47 years, and two of the affected individuals also developed nearly concurrent symptoms of spasticity (Dumanchin et al., 2006).

This variant was absent from the gnomAD variant database (gnomAD v2.1.1).

Neuropathology

Neuropathological examination of two brains revealed widespread neurofibrillary tangles and numerous plaques, including both large, non-neuritic cotton-wool plaques and neuritic plaques more typical of AD. Marked cerebral amyloid angiopathy was also observed (Dumanchin et al., 2006).

Biological Effect

Analysis of patient mRNA extracted from peripheral blood cells and analyzed by RT-PCR followed by ethidium bromide gel separation showed transcripts lacking exon 9. Ex vivo splicing assays confirmed these results in HeLa cells and in the neuroblastoma cell line SH-SY5Y (Dumanchin et al., 2006). 

A summary of the biological effects of PSEN1 mutants that result in the exclusion of exon 9 can be found at: PSEN1 ΔE9 Mutants (below the table).

Although several in silico algorithms predicted this variant is damaging (Xiao et al., 2021), its PHRED-scaled CADD score, which integrates diverse information, was only 7.7 (CADD v.1.6, Sep 2021).

Pathogenicity

Alzheimer's Disease : Not Classified*

*This variant fulfilled some ACMG-AMP criteria, but it is not classified by Alzforum because only one affected carrier has been reported, and the variant is absent from the gnomAD database. Note that multiple mutations resulting in the same consequence (deletion of exon 9) are pathogenic.

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

PS3-S

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. c.869-22_869-23ins18: Functional data derive from assays involving exon 9 deletion mutants, not necessarily this specific variant.

PM1-M

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.

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.

PM4-M

Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.

BP4-P

Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc). *In most cases, Alzforum applies this criterion when the variant’s PHRED-scaled CADD score is less than 20.

Pathogenic (PS, PM, PP) Benign (BA, BS, BP)
Criteria Weighting Strong (-S) Moderate (-M) Supporting (-P) Supporting (-P) Strong (-S) Strongest (BA)

Research Models

A summary of research models that express PSEN1 lacking exon 9 can be found at: PSEN1 ΔE9 Mutants (below the table).

Last Updated: 14 Oct 2023

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

Paper Citations

  1. Dumanchin C, Tournier I, Martin C, Didic M, Belliard S, Carlander B, Rouhart F, Duyckaerts C, Pellissier JF, Latouche JB, Hannequin D, Frebourg T, Tosi M, Campion D. Biological effects of four PSEN1 gene mutations causing Alzheimer disease with spastic paraparesis and cotton wool plaques. Hum Mutat. 2006 Oct;27(10):1063. PubMed.
  2. Xiao X, Liu H, Liu X, Zhang W, Zhang S, Jiao B. APP, PSEN1, and PSEN2 Variants in Alzheimer's Disease: Systematic Re-evaluation According to ACMG Guidelines. Front Aging Neurosci. 2021;13:695808. Epub 2021 Jun 18 PubMed.

Other Citations

  1. PSEN1 ΔE9 Mutants

External Citations

  1. gnomAD v2.1.1

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. Dumanchin C, Tournier I, Martin C, Didic M, Belliard S, Carlander B, Rouhart F, Duyckaerts C, Pellissier JF, Latouche JB, Hannequin D, Frebourg T, Tosi M, Campion D. Biological effects of four PSEN1 gene mutations causing Alzheimer disease with spastic paraparesis and cotton wool plaques. Hum Mutat. 2006 Oct;27(10):1063. PubMed.

PSEN1 ΔE9 Mutants

View Table

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.