Overview

Pathogenicity: Alzheimer's Disease : Pathogenic, Frontotemporal Dementia : Not Classified
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease, Frontotemporal Dementia
Position: (GRCh38/hg38):Chr14:73171047 T>C
Position: (GRCh37/hg19):Chr14:73637755 T>C
dbSNP ID: rs63751399
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CTA to CCA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 4

Findings

This mutation was identified in a French family known as SAL 513. The reported pedigree consisted of six family members affected by early onset dementia across four generations. The inheritance pattern was consistent with autosomal-dominant inheritance. Ages of onset were 38, 39, 40, 45, and 50 years for the five family members for whom data was reported. The disease manifested with behavioral impairments, including impulsiveness and stereotyped behavior, as well as changes in mood and personality, and loss of personal and social awareness. Myoclonic jerks and seizures appeared later. Three affected members of the family fulfilled the Lund and Manchester criteria for frontotemporal dementia (Lund and Manchester Group, 1994) and consensus criteria for FTD (Neary et al., 1998). However, others have suggested the mutation may cause a frontal variant of AD, rather than FTD, since neuropathology includes plaques and tangles typical of AD (Bergmans and De Strooper, 2010, July 2012 webinar).

The mutation was detected in the two affected family members screened and absent in a healthy 67-year-old sister of the proband, supporting segregation of the mutation with disease (Raux et al., 2000). The variant was absent from the gnomAD variant database (gnomAD v2.1.1, May 2021).

Neuropathology

CT scans from two patients showed predominant frontotemporal atrophy and SPECT showed hypoperfusion including the frontal lobes (Raux et al., 2000). In addition, AD-like plaques and tangles were reported (Bergmans and De Strooper, 2010).

Biological Effect

L113 has been identified as key for PSEN1's γ-processivity, the carboxypeptidase activity that trims Aβ intermediates to form shorter, secreted speices, and this mutant appears to reduce it (Liu et al., 2021). Analysis of secreted Aβs in the conditioned media of human embryonic kidney cells lacking endogenous PSENs and expressing this mutant along with wildtype APP, revealed increased Aβ42/40 ratio, and decreased Aβ37/40, Aβ37/42, and Aβ38/42 ratios. Interestingly, the authors also reported that Aβ42/40, Aβ38/42, and particularly Aβ37/42, ratios each correlated with reported ages of onset of clinical impairment across 16 PSEN1 mutations. This mutant also reduced total secreted Aβ levels. Of note, the authors proposed this residue as a key target for heterocyclic γ-secretase modulators (GSMs) to stimulate processing of pathogenic Aβ peptides.

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)

Pathogenicity

Alzheimer's Disease : Pathogenic*

*Affected carriers seem to have a frontal variant of AD, originally diagnosed as FTD.

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

PS3-S

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.

PM1-P

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. L113P: Variant located at edge of mutational hot spot.

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.

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. L113P: 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: 22 Feb 2022

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References

Webinar Citations

Paper Citations

Clinical and neuropathological criteria for frontotemporal dementia. The Lund and Manchester Groups. J Neurol Neurosurg Psychiatry. 1994 Apr;57(4):416-8. PubMed.
Neary D, Snowden JS, Gustafson L, Passant U, Stuss D, Black S, Freedman M, Kertesz A, Robert PH, Albert M, Boone K, Miller BL, Cummings J, Benson DF. Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology. 1998 Dec;51(6):1546-54. PubMed.
Bergmans BA, De Strooper B. gamma-secretases: from cell biology to therapeutic strategies. Lancet Neurol. 2010 Feb;9(2):215-26. PubMed.
Raux G, Gantier R, Thomas-Anterion C, Boulliat J, Verpillat P, Hannequin D, Brice A, Frebourg T, Campion D. Dementia with prominent frontotemporal features associated with L113P presenilin 1 mutation. Neurology. 2000 Nov 28;55(10):1577-8. PubMed.
Liu L, Lauro BM, Wolfe MS, Selkoe DJ. Hydrophilic loop 1 of Presenilin-1 and the APP GxxxG transmembrane motif regulate γ-secretase function in generating Alzheimer-causing Aβ peptides. J Biol Chem. 2021;296:100393. Epub 2021 Feb 8 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 L113P

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