Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease, Spastic Paraparesis
Position: (GRCh38/hg38):Chr14:73192804 T>A
Position: (GRCh37/hg19):Chr14:73659512 T>A
dbSNP ID: rs63750858
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: TTT to ATT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This mutation was found in a Japanese man with very early onset AD with spastic paraparesis, but no known family history of the disease (Sodeyama et al., 2001). His first neurological symptom was gait disturbance at age 31. A year later, he developed memory loss and cognitive impairment, both of which progressed rapidly, with dementia diagnosed at age 33. Also at 33, he presented with diffuse hyperreflexia, ataxia in all limbs, and bilateral Babinski’s sign. None of the proband’s known family members had developed similar symptoms, and none were tested for the mutation. The mutation was absent from 197 Japanese patients, including 73 non-demented controls without a CNS disorder and 59 patients with sporadic AD, as well as from the gnomAD variant database (gnomAD v2.1.1, July 2021).

Neuropathology
Neuropathological data are unavailable, but 2DG-PET and SPECT imaging of the proband’s brain showed metabolic and perfusion patterns typical of AD, with hypometabolism and hypoperfusion in the bilateral temporoparietal areas, including the primary sensory and motor cortices (Sodeyama et al., 2001). MRI revealed diffuse cerebral cortical atrophy.

Biological Effect
In an in vitro assay using APP C99 as a substrate, Aβ42 production was severely inhibited and Aβ40 was undetectable (Bai et al., 2015). A subsequent in vitro study also found decreased production of both Aβ40 and Aβ42, and the Aβ42/Aβ40 ratio was similar to that generated by wild-type PSEN1 (Sun et al., 2017). Moreover, a study that examined a range of Aβ peptides produced by human embryonic kidney cells expressing this mutant and lacking endogenous PSEN1 and PSEN2 also revealed an Aβ42/Aβ40 ratio similar to controls, but the Aβ37/Aβ42 ratio, another indicator of reduced Aβ trimming activity, was decreased (Liu et al., 2022; Apr 2022 news). In this study, Aβ37/Aβ42 outperformed Aβ42/Aβ40 as a biomarker for distinguishing between control and AD samples. Also, as in the other studies, the levels of Aβ42 and Aβ40 were reduced compared with controls, as was Aβ43.

Codon 237 is evolutionarily conserved in human PSEN1, human PSEN2, mouse PSEN1, and Caenorhabditis elegans Sel-12 protein (Sodeyama et al., 2001). Moreover, a cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates that, in wild-type PSEN1, the phenylalanine at this position helps form a hydrophobic pocket in the substrate-binding pore (Zhou et al., 2019; Jan 2019 news). As described in another cryo-EM study, substitution of phenylalanine with isoleucine, a smaller hydrophobic residue, is expected to reduce the strength of the PSEN1-APP hydrophobic interaction (Guo et al., 2024; Jun 2024 news).

Several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) predicted this variant is damaging (Xiao et al., 2021). Moreover, a pathogenic mutation, F237L, has been identified at the same amino acid position.

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.

PS3-M

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. F237I: Decreased Aβ37/Aβ42 ratio; Aβ42/Aβ40 ratio similar to wildtype. Decreased levels of Aβ43, Aβ42, Aβ40.

PM1-S

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. F237I: Variant is in a mutational hot spot and cryo-EM data suggest residue is of functional importance.

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.

PM5-M

Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.

PP2-P

Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.

PP3-P

Multiple lines of computational evidence support a deleterious effect on the 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 greater than or equal to 20.

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

Last Updated: 13 Jun 2024

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References

News Citations

Mutations Citations

Paper Citations

Sodeyama N, Iwata T, Ishikawa K, Mizusawa H, Yamada M, Itoh Y, Otomo E, Matsushita M, Komatsuzaki Y. Very early onset Alzheimer's disease with spastic paraparesis associated with a novel presenilin 1 mutation (Phe237Ile). J Neurol Neurosurg Psychiatry. 2001 Oct;71(4):556-7. PubMed.
Bai XC, Yan C, Yang G, Lu P, Ma D, Sun L, Zhou R, Scheres SH, Shi Y. An atomic structure of human γ-secretase. Nature. 2015 Sep 10;525(7568):212-7. Epub 2015 Aug 17 PubMed.
Sun L, Zhou R, Yang G, Shi Y. Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase. Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E476-E485. Epub 2016 Dec 5 PubMed.
Liu L, Lauro BM, He A, Lee H, Bhattarai S, Wolfe MS, Bennett DA, Karch CM, Young-Pearse T, Dominantly Inherited Alzheimer Network (DIAN), Selkoe DJ. Identification of the Aβ37/42 peptide ratio in CSF as an improved Aβ biomarker for Alzheimer's disease. Alzheimers Dement. 2022 Mar 12; PubMed.
Zhou R, Yang G, Guo X, Zhou Q, Lei J, Shi Y. Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
Guo X, Li H, Yan C, Lei J, Zhou R, Shi Y. Molecular mechanism of substrate recognition and cleavage by human γ-secretase. Science. 2024 Jun 7;384(6700):1091-1095. Epub 2024 Jun 6 PubMed.
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.

Mutations

PSEN1 F237I

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