Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease, PSP/CBS
Position: (GRCh38/hg38):Chr14:73170972 C>G
Position: (GRCh37/hg19):Chr14:73637680 C>G
dbSNP ID: rs1897874329
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CCT to CGT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 4

Findings

This variant was identified in a woman of Moroccan ancestry suffering from symptoms reminiscent of progressive supranuclear palsy (Thomas et al., 2022). Symptoms included parkinsonism with difficulty initiating movement and rigidity, foot dystonia, spastic paraparesis, postural instability, frontal dementia, and supranuclear gaze palsy. Her first symptoms, abnormal gait and rapid weight loss, emerged at age 51 and by 54 she was wheelchair-bound. She subsequently developed epileptic seizures and died at age 55. Her mother had developed similar symptoms and also died before age 60, and her son had psychiatric problems.

Despite her PSP-like clinical phenotype, the patient was diagnosed with “PSEN1-associated Alzheimer’s disease” because singleton exome sequencing revealed she carried the PSEN1 P88R variant, and she had cerebrospinal fluid and brain imaging biomarkers of AD (see below).

Of note, carriers of another mutation at this position, P88L, have also been reported to have atypical clinical phenotypes that include multiple motor impairments.

This variant was absent from the ExAC and gnomAD variant databases.

Neuropathology
Neuropathological data are unavailable, but an MRI brain scan of the proband revealed bilateral temporal and parietal atrophy with abundant white matter hyperintensities (Thomas et al., 2022). In addition, cerebrospinal fluid levels of Aβ42 and the Aβ42/Aβ40 ratio were reduced, as occurs in AD, although total tau and phosphorylated tau levels were normal. Brain imaging of dopamine transporters (DAT) showed no signs of dopaminergic denervation.

Biological Effect
The biological effect of this variant is unknown, but several observations indicate it may be deleterious. A cryo-electron microscopy study suggests P88 functions as a hinge, allowing the highly dynamic transmembrane domain 1 of PSEN1 to bend towards the APH-1 subunit of the γ-secretase complex (Odorčić et al., 2024; Jun 2024 news). Also, in silico algorithms, including CADD (PHRED-scaled score = 32), predicted it is deleterious (Thomas et al., 2022).  Moreover, the variant is at a position where a pathogenic variant was previously reported, P88L, and the amino acid is highly conserved.

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.

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References

Mutations Citations

1. PSEN1 P88L

News Citations

1. Caught in the Act: Cryo-EM Exposes γ-Secretase Catalytic Pose 7 Jun 2024

Paper Citations

1. Thomas Q, Nambot S, Béjot Y, Philippe C, Faivre L, Duffourd Y, Thauvin-Robinet C, Dupont G. A New Presenilin-1 Missense Variant Associated With a Progressive Supranuclear Palsy-like Phenotype. Alzheimer Dis Assoc Disord. 2022 Mar 30; PubMed.
2. Odorčić I, Hamed MB, Lismont S, Chávez-Gutiérrez L, Efremov RG. Apo and Aβ46-bound γ-secretase structures provide insights into amyloid-β processing by the APH-1B isoform. Nat Commun. 2024 May 27;15(1):4479. PubMed.

Further Reading

No Available Further Reading