Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PS4, PM1, PM2, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73170972 C>T
Position: (GRCh37/hg19):Chr14:73637680 C>T
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CCT to CTT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 4

Findings

This mutation was found in two Caucasian sisters clinically diagnosed with early onset Alzheimer’s disease (Liu et al., 2017). The proband began exhibiting symptoms of myoclonus in her 20s and of memory difficulties at age 41. Her cognition declined rapidly, and by age 45 she was severely demented. Additional clinical features included Parkinsonism, spasticity, ataxia, apraxia, and dystonia. The proband’s younger sister, who also carried the P88L mutation, exhibited myoclonus followed by cognitive decline. The mother of the two affected sisters was cognitively normal at age 63, and she did not carry this mutation.

A Caucasian woman living in Spain was also found to carry the mutation and suffer from an atypical clinical phenotype (Vázquez-Costa et al., 2021). Motor impairments—starting with dysarthria at age 45 followed by dysphagia, gait imbalance, and generalized upper motor neuron signs predominant in the lower limbs two years later--emerged prior to cognitive and behavioral symptoms. The carrier was first diagnosed with progressive pseudobulbar palsy, followed by tentative diagnoses of primary lateral sclerosis and frontotemporal dementia. Ultimately, she was diagnosed with autosomal dominant AD after identification of the P88L mutation by sequence analysis using a panel of 5,227 genes involved in rare inherited disorders. The proband’s mother, who died at age 64, was diagnosed with dementia at 59 or 60.

A Japanese woman with AD onset at 52 years of age was also reported as carrying the mutation (Islam et al., 2022). She had reduced ApoE levels in blood, despite having an APOE3/3 genotype which is not associated with decreased ApoE. The authors hypothesized that the reduction could be due to a disruption of PSEN1’s proposed role in ApoE secretion.

The mutation was not found in the 1000 Genomes, Exome Variant Server, ExAC, or gnomAD variant databases (Liu et al., 2017).

Neuropathology

Neuropathological data are unavailable. However, MRI of one carrier revealed generalized cortical atrophy, FDG-PET showed hypometabolism in putamina and temporo-parietal regions, and CSF biomarkers (low Aβ42 and elevated total- and phospho-tau) were consistent with the diagnosis of AD (Liu et al., 2017). MRI and CSF biomarker analyses in a second carrier yielded similar results, with FDG-PET showing an asymmetric decrease of glucose uptake in frontoparietal areas, including the motor cortex (Vázquez-Costa et al., 2021).

Biological Effect

The effect of the PSEN1 P88L mutation on Aβ generation was studied in stably transfected fibroblasts from double-knockout Psen1/Psen2 mice (Ohki et al., 2014). PSEN1 P88L resulted in an increased ratio of Aβ42,43/Aβ40, compared with cells transfected with wild-type PSEN1. In addition, cells expressing the P88L mutant secreted Aβ45 and Aβ46, two species not generated by cells expressing wild-type PSEN1 (these studies were performed prior to the identification of P88L as a causal mutation in early onset AD, and the nucleotide change giving rise to the proline-to-leucine substitution was not specified). Moreover, assays using purified PSEN1 complexes and a tagged APPC99 substrate revealed P88L is more sensitive to elevated temperatures than the wild-type protein (Szaruga et al., 2017). This suggests the mutation consistently destabilizes the interaction required for proteolysis of APPC99 and newly produced Aβn substrates, resulting in the release of longer Aβ peptides.

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). The substitution of a proline, which enables kink formation, by a leucine, which promotes helix formation, likely interferes with the sequential catalysis that trims Aβ peptides causing the release of longer peptides such as Aβ45 and Aβ46.

The CADD-PHRED tool, which integrates diverse in silico information, gave it a high deleteriousness score above 20 (CADD v.1.6, Sep 2021). Consistent with this score, multiple in silico algorithms predicted this variant is damaging (Liu et al., 2017, Xiao et al., 2021).

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.

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References

News Citations

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

Paper Citations

1. Liu CY, Ohki Y, Tomita T, Osawa S, Reed BR, Jagust W, Van Berlo V, Jin LW, Chui HC, Coppola G, Ringman JM. Two Novel Mutations in the First Transmembrane Domain of Presenilin1 Cause Young-Onset Alzheimer's Disease. J Alzheimers Dis. 2017;58(4):1035-1041. PubMed.
2. Vázquez-Costa JF, Payá-Montes M, Martínez-Molina M, Jaijo T, Szymanski J, Mazón M, Sopena-Novales P, ENoD Consortium, Pérez-Tur J, Sevilla T. Presenilin-1 Mutations Are a Cause of Primary Lateral Sclerosis-Like Syndrome. Front Mol Neurosci. 2021;14:721047. Epub 2021 Aug 30 PubMed.
3. Islam S, Sun Y, Gao Y, Nakamura T, Noorani AA, Li T, Wong PC, Kimura N, Matsubara E, Kasuga K, Ikeuchi T, Tomita T, Zou K, Michikawa M. Presenilin Is Essential for ApoE Secretion, a Novel Role of Presenilin Involved in Alzheimer's Disease Pathogenesis. J Neurosci. 2022 Feb 23;42(8):1574-1586. Epub 2022 Jan 5 PubMed.
4. Ohki Y, Shimada N, Tominaga A, Osawa S, Higo T, Yokoshima S, Fukuyama T, Tomita T, Iwatsubo T. Binding of longer Aβ to transmembrane domain 1 of presenilin 1 impacts on Aβ42 generation. Mol Neurodegener. 2014 Jan 13;9:7. PubMed.
5. Szaruga M, Munteanu B, Lismont S, Veugelen S, Horré K, Mercken M, Saido TC, Ryan NS, De Vos T, Savvides SN, Gallardo R, Schymkowitz J, Rousseau F, Fox NC, Hopf C, De Strooper B, Chávez-Gutiérrez L. Alzheimer's-Causing Mutations Shift Aβ Length by Destabilizing γ-Secretase-Aβn Interactions. Cell. 2017 Jul 27;170(3):443-456.e14. PubMed. Correction.
6. 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.
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.

Further Reading

No Available Further Reading