Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS1, PS3, PM1, PM2, PP1, PP3
Clinical Phenotype: Alzheimer's Disease, Spastic Paraparesis
Position: (GRCh38/hg38):Chr14:73206385 G>T
Position: (GRCh37/hg19):Chr14:73673093 G>T
dbSNP ID: rs63750219 
Coding/Non-Coding: Both
DNA Change: Substitution
Expected RNA Consequence: Splicing Alteration
Expected Protein Consequence: Deletion-Insertion
Genomic Region: Intron 8, Exon 9

Findings

This point mutation at a splice site in intron 8 was the first mutation in PSEN1 determined to result in the deletion of exon 9 from mRNA transcripts. Now, several unique mutations have been identified that result in the exclusion of exon 9 and are variously known as ΔE9, Δ9, delE9, or deltaE9. This deletion occurs in-frame, so presenilin protein is produced, but it lacks amino acids 290-319.

This mutation was first identified in a British family known as F74 (Perez-Tur et al., 1995). The reported pedigree contains seven affected individuals over three generations with symptoms typical of early onset AD, with onset ranging from 39 to 50 years of age. Disease in this family had previously been shown to be linked to chromosome 14, but the precise genetic lesion had been elusive. The mutation was shown to segregate with disease in this family (it was present in three affected individuals and absent in five unaffected). It was also absent in 100 control individuals. This family was described in Hutton et al., 1996.

This mutation was also identified in a pedigree known as EOFAD-3 whose affected members met NINCDS-ADRDA criteria for probable AD (Kwok et al., 1997). This pedigree was also affected by familial spastic paraparesis, a rare neurodegenerative disorder of the central motor system characterized by progressive spasticity of the lower limbs. Spastic paraparesis and AD co-occurred, but also appeared separately. The mean age of onset was reported as 44.4 years (ranging from 41 to 47 years) and it was noted that the dementia was typically less prominent in individuals with spasticity. Further clinical details and associated pathology are reported in Brooks et al., 2003.

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

Neuropathology

Neuropathological examination of two brains from the EOFAD-3 family revealed numerous cotton-wool plaques throughout the neocortex. Cored plaques were less frequent. Neurofibrillary tangles, neuronal loss, gliosis, and cerebral amyloid angiopathy also were noted. Both cases fulfilled NIA-Reagan criteria for AD (Brooks et al., 2003).

Cotton-wool plaques also were noted in two additional cases with exon 9 deletion who had died at age 52 and 59, respectively. However, it was not clear from the report which exon 9 deletion mutation these individuals carried. Over all, these cases had frequent plaques and neurofibrillary tangles (a Braak score of 5 in both). One of the cases also had Pick bodies in the dentate gyrus; no other brain regions were examined (Halliday et al., 2005).

Biological Effect

This point mutation abrogates the splice acceptor site so that exon 9 (encoding residues 290-319) is spliced out of mature transcripts (Perez-Tur et al., 1995). The skipping of exon 9 occurs in-frame and also results in an amino acid change at the splice junction of exon 8 and 10 (S290C).

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).

Pathogenicity

Alzheimer's Disease : Pathogenic

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

Research Models

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

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References

Paper Citations

1. Perez-Tur J, Froelich S, Prihar G, Crook R, Baker M, Duff K, Wragg M, Busfield F, Lendon C, Clark RF. A mutation in Alzheimer's disease destroying a splice acceptor site in the presenilin-1 gene. Neuroreport. 1995 Dec 29;7(1):297-301. PubMed.
2. Hutton M, Busfield F, Wragg M, Crook R, Perez-Tur J, Clark RF, Prihar G, Talbot C, Phillips H, Wright K, Baker M, Lendon C, Duff K, Martinez A, Houlden H, Nichols A, Karran E, Roberts G, Roques P, Rossor M, Venter JC, Adams MD, Cline RT, Phillips CA, Goate A. Complete analysis of the presenilin 1 gene in early onset Alzheimer's disease. Neuroreport. 1996 Feb 29;7(3):801-5. PubMed.
3. Kwok JB, Taddei K, Hallupp M, Fisher C, Brooks WS, Broe GA, Hardy J, Fulham MJ, Nicholson GA, Stell R, St George Hyslop PH, Fraser PE, Kakulas B, Clarnette R, Relkin N, Gandy SE, Schofield PR, Martins RN. Two novel (M233T and R278T) presenilin-1 mutations in early-onset Alzheimer's disease pedigrees and preliminary evidence for association of presenilin-1 mutations with a novel phenotype. Neuroreport. 1997 Apr 14;8(6):1537-42. PubMed.
4. Brooks WS, Kwok JB, Kril JJ, Broe GA, Blumbergs PC, Tannenberg AE, Lamont PJ, Hedges P, Schofield PR. Alzheimer's disease with spastic paraparesis and 'cotton wool' plaques: two pedigrees with PS-1 exon 9 deletions. Brain. 2003 Apr;126(Pt 4):783-91. PubMed.
5. Halliday GM, Song YJ, Lepar G, Brooks WS, Kwok JB, Kersaitis C, Gregory G, Shepherd CE, Rahimi F, Schofield PR, Kril JJ. Pick bodies in a family with presenilin-1 Alzheimer's disease. Ann Neurol. 2005 Jan;57(1):139-43. PubMed.

Other Citations

1. PSEN1 ΔE9 Mutants

External Citations

1. gnomAD v2.1.1

Further Reading