Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS1, PS3, PS4, PM1, PM2, PP1, PP3
Clinical Phenotype: Alzheimer's Disease, Spastic Paraparesis
Position: (GRCh38/hg38):Chr14:73206385 G>A
Position: (GRCh37/hg19):Chr14:73673093 G>A
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 results in the exclusion of exon 9 from mRNA transcripts. It is one of several known mutations that result in exon 9 exclusion, which are known as ΔE9, delE9, E9, or deltaE9. This specific mutation (G>A) has been detected in four families with very  different ancestries. A similar point mutation (G>T) at the same position has also been reported in two families and appears to have a similar effect on splicing.

The G>A mutation was first reported in a large Japanese pedigree known as TK-1 (Sato et al., 1998). The reported pedigree shows 11 affected family members over five generations. The mean age of onset in this family was reported as 47.50 ± 3.29 and the mean age at death was 54.62 ± 4.37. Symptoms included classic features of AD (e.g., memory impairment, lack of spontaneity, disorientation), but also some extrapyramidal signs and a progressive form of spastic paralysis with rigidity which started in the lower limbs.

The mutation appeared to segregate with disease in TK-1. Of the 11 family members examined, the mutation was present in the proband and in four asymptomatic individuals under the mean age of onset for the family. The mutation was absent in six unaffected family members and in 98 healthy Japanese controls.

The second pedigree, an Australian family known as EOFAD-2, were of Anglo-Celtic origin (Brooks et al., 2003). The reported pedigree shows 14 affected individuals over four generations. The clinical phenotype consisted of progressive cognitive decline with some individuals displaying symptoms of spastic paraparesis (spasticity of the lower limbs, gait disturbance, etc.). The mean onset age was 44.9 years (range: 36 to 52 years) with a trend toward those individuals with spasticity displaying a slightly later onset. A diagnosis of AD was confirmed by autopsy in four individuals. The G>A splice acceptor mutation was found in the proband and test results from 11 other members of the EOFAD-2 family were consistent with segregation of the mutation with the disease phenotype (dementia, spastic paraparesis, or both) in an autosomal-dominant manner.

The mutation was also found in a U.K. genetic screen of patients with dementia (Koriath et al., 2018). The family of the mutation carrier had at least three members, including a first-degree relative, diagnosed with AD across two generations. The carrier’s AD symptoms emerged at age 57.

In addition, the mutation was identified in two male siblings of a Turkish family including 39 members spanning four generations with nine affected individuals (Doğan et al., 2022). The carriers' first clinical symptom was memory impairment, surfacing at ages 40 and 38 years. Both men also suffered from behavioral symptoms, delusions/hallucinations, spastic paraparesis, and myoclonus. 

This mutation was absent from genetic variant databases, including ExAC and gnomAD.

Neuropathology

Two cases from the TK-1 family were examined neuropathologically (Tabira et al., 2002). The subjects were identical twin brothers with clinical histories typical of their family, including onset at age 45 and 46. One brother developed memory disturbances at age 45, followed by spastic paraparesis with muscular rigidity. He deteriorated gradually, becoming severely demented, with myoclonus and epilepsy, and died at age 64. The other brother first reported trembling and lower leg pain at age 46. His memory impairment became apparent later, developing over time into severe dementia. He also developed progressive spastic paraplegia with myoclonus and seizures. He died at age 61.

In both cases senile plaques were numerous in the hippocampus, frontal, temporal, and parietal cortices, moderate in the occipital cortex, and mild in the cerebellar cortex and the inferior olive. Some plaques had an amyloid core, and mild neuritic changes were observed. Neurofibrillary tangles were likewise abundant and amyloid angiopathy was scattered. Cotton-wool plaques could be seen by hematoxylin and eosin staining. The neuropathology of one of these cases was further investigated in the context of comparison to other mutations that involve exon 9 exclusion (Mann et al., 2001).

Neuropathological findings are also available from four cases within the EOFAD-2 kindred (Brooks et al., 2003). All four cases were affected by early onset dementia, but none had reported symptoms of spasticity. The neuropathology in all four was sufficient to meet NIA-Reagan criteria for Alzheimer's disease, with numerous neurofibrillary tangles and plaques in the hippocampus and cerebral cortex, and neuronal loss throughout the cortex. The plaques were both of the large, cotton-wool type and the neuritic type. Congophilic angiopathy was also noted as being present in all four brains.

Magnetic resonance imaging of the brains of the two Turkish carriers revealed atrophy in the parahippocampal gyrus (Doğan et al., 2022).

Biological Effect

This point mutation occurs at a splice acceptor site in intron 8 and causes aberrant splicing leading to the generation of PSEN1 mRNA lacking exon 9 and proteins that lack 28 amino acid residues (291-319). The mutation also causes an amino acid change (S290C) at the splice junction of exons 8 and 10. Koriath and colleagues reported a CADD score of 26.7, predicted to be amongst the top one percent of deleterious variants in the human genome (Koriath et al., 2018), and Xiao and colleagues reported multiple in silico algorithms predicted the mutation was damaging (Xiao et al., 2021).

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. Sato S, Kamino K, Miki T, Doi A, Ii K, St George-Hyslop PH, Ogihara T, Sakaki Y. Splicing mutation of presenilin-1 gene for early-onset familial Alzheimer's disease. Hum Mutat. 1998;Suppl 1:S91-4. PubMed.
2. 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.
3. Koriath C, Kenny J, Adamson G, Druyeh R, Taylor W, Beck J, Quinn L, Mok TH, Dimitriadis A, Norsworthy P, Bass N, Carter J, Walker Z, Kipps C, Coulthard E, Polke JM, Bernal-Quiros M, Denning N, Thomas R, Raybould R, Williams J, Mummery CJ, Wild EJ, Houlden H, Tabrizi SJ, Rossor MN, Hummerich H, Warren JD, Rowe JB, Rohrer JD, Schott JM, Fox NC, Collinge J, Mead S. Predictors for a dementia gene mutation based on gene-panel next-generation sequencing of a large dementia referral series. Mol Psychiatry. 2018 Oct 2; PubMed.
4. Doğan M, Eröz R, Tecellioğlu M, Gezdirici A, Çevik B, Barış İ. Clinical and Molecular Findings in a Turkish Family Who Had a (c.869- 1G>A) Splicing Variant in PSEN1 Gene with A Rare Condition: The Variant Alzheimer's Disease with Spastic Paraparesis. Curr Alzheimer Res. 2022;19(3):223-235. PubMed.
5. Tabira T, Chui DH, Nakayama H, Kuroda S, Shibuya M. Alzheimer's disease with spastic paresis and cotton wool type plaques. J Neurosci Res. 2002 Nov 1;70(3):367-72. PubMed.
6. Mann DM, Takeuchi A, Sato S, Cairns NJ, Lantos PL, Rossor MN, Haltia M, Kalimo H, Iwatsubo T. Cases of Alzheimer's disease due to deletion of exon 9 of the presenilin-1 gene show an unusual but characteristic beta-amyloid pathology known as 'cotton wool' plaques. Neuropathol Appl Neurobiol. 2001 Jun;27(3):189-96. PubMed.
7. 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

Further Reading