Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS1, PS4, PM1, PM2, PM5, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73653599 G>C
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: TTG to TTC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 6

Findings

This mutation was detected in two Japanese siblings from a family affected by early onset Alzheimer's disease (Kasuga et al., 2009). The reported pedigree shows six affected individuals over three generations. The proband and her affected sister were heterozygous carriers, suggesting segregation with disease. In this family, depression and psychiatric symptoms preceded cognitive decline. The proband was treated for depression at age 29. By age 48 she had developed personality changes and visual and auditory hallucinations. She also developed parkinsonian symptoms, including rigidity and postural instability. Her sister experienced a similar disease course, starting with depression and bipolar symptoms as an adolescent. By age 40 she had developed cognitive decline as well as parkinsonism.

The variant was also reported in two Chinese families with familial Alzheimer's disease (Jia et al., 2020). One family had six affected members, spanning two generations, including two affected carriers and one unaffected non-carrier who was 52 years old, past the family's mean age at onset of 42. The two carriers were APOE3 homozygotes. The other family included four affected members, spanning two generations. The variant was identified in three of the affected carriers. Mean age at onset in this family was 39. Of note, the proband's APOE genotype was E4/E4.

The mutation was absent from the gnomAD variant database (gnomAD v2.1.1, June 2021).

Neuropathology

Unknown. MRI in both Japanese sisters showed atrophy of the medial temporal lobe (Kasuga et al., 2009). SPECT showed hypoperfusion of the posterior cingulate gyri and other cortical areas.

Compared with carriers of other familial AD mutations, an L173F carrier (nucleotide change unspecified) had a similar ratio of Aβ38/Aβ40 in their cerebrospinal fluid, with both peptides present at very low levels (Kakuda et al., 2021). Also, both Aβ42 and Aβ43 levels were very low.

Biological Effect

How this variant affects Aβ peptide production, and thus pathogenicity, is uncertain. Kasuga and colleagues originally reported that N2a cells transfected with mutant PSEN1 secreted significantly more Aβ42 than cells expressing wild-type PSEN1 and had an elevated Aβ42/Aβ40 ratio (Kasuga et al., 2009). A subsequent cell-based study also found this variant (nucleotide change unspecified) increased the Aβ42/Aβ40 ratio, but reduced production of both Aβ42 and Aβ40 (Liu et al., 2022; Apr 2022 news). Moreover, in this same study, the Aβ37/Aβ42 ratio, a measurement that outperformed the Aβ42/Aβ40 ratio as a biomarker for distinguishing between control and AD samples, was similar to that of controls.

A cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates this residue is apposed to the APP transmembrane helix, with its side-chain reaching towards the interior of the substrate-binding pore (Zhou et al., 2019; Jan 2019 news).

Several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, PANTHER, Mutpred2, and Reve in the VarCards database) predicted this variant is damaging (Jia et al., 2020, Xiao et al., 2021). Jia and colleageues reported a PHRED-CADD score of 24.3.

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.

PS1-S

Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.

PS4-M

The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. L173F (G>C): The variant was reported in 3 or more unrelated patients with the same phenotype, and absent from controls.

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. L173F (G>C): 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.

PP1-M

Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease: *Alzforum requires at least one affected carrier and one unaffected non-carrier from the same family to fulfill this criterion. L173F (G>C): At least one family with 2 affected carriers and >=1 unaffected noncarriers.

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: 09 Nov 2022

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References

News Citations

Paper Citations

Kasuga K, Ohno T, Ishihara T, Miyashita A, Kuwano R, Onodera O, Nishizawa M, Ikeuchi T. Depression and psychiatric symptoms preceding onset of dementia in a family with early-onset Alzheimer disease with a novel PSEN1 mutation. J Neurol. 2009 Aug;256(8):1351-3. PubMed.
Jia L, Fu Y, Shen L, Zhang H, Zhu M, Qiu Q, Wang Q, Yan X, Kong C, Hao J, Wei C, Tang Y, Qin W, Li Y, Wang F, Guo D, Zhou A, Zuo X, Yu Y, Li D, Zhao L, Jin H, Jia J. PSEN1, PSEN2, and APP mutations in 404 Chinese pedigrees with familial Alzheimer's disease. Alzheimers Dement. 2020 Jan;16(1):178-191. PubMed.
Kakuda N, Takami M, Okochi M, Kasuga K, Ihara Y, Ikeuchi T. Switched Aβ43 generation in familial Alzheimer's disease with presenilin 1 mutation. Transl Psychiatry. 2021 Nov 3;11(1):558. 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.
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 L173F (G>C)

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