Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PS4, PM1, PM2, PM5, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73173577 C>T
Position: (GRCh37/hg19):Chr14:73640285 C>T
dbSNP ID: rs63749805
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CCA to CTA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 5
Research Models: 1

Findings

This mutation was originally identified in a Polish family with a history of Alzheimer’s disease (Wisniewski et al., 1998). The reported pedigree had four affected family members over two generations, all of whom fulfilled NINCDS-ADRDA criteria for probable AD and two of whom had autopsy-confirmed AD. This mutation is associated with a particularly early age at onset and age at death. Ages of onset in this family were 24, 32, 32, and 33 (mean 30.25 years). The presenting symptoms were progressive memory loss and alterations in mood. Ages at death were 28, 35, 37, and 37 years (mean 34.25 years). The P117L mutation segregated with disease in this family; it was found in all affected family members and was absent in unaffected family members. It was absent in 30 unrelated individuals. No mutations were found in PSEN2 or APP

This mutation was later found in a 33-year-old man who presented with mood disturbances, memory problems, and apraxia (Alberici et al., 2007). Other symptoms included seizures, extrapyramidal rigidity, myoclonic jerks in the upper limbs, disinhibition, euphoria, delusions, and hallucinations. A possible diagnosis of the lysosomal-storage disease neuronal ceroid lipofuscinosis (NCL) was considered, given the patient's clinical symptoms and the presence of granular osmiophilic deposits in a skin biopsy. However, he was considered to have AD with possibly overlapping NCL. This patient did not have a family history of dementia and his parents were not mutation carriers. Microsatellite typing confirmed paternity, strongly suggesting the mutation occurred de novo. No additional mutations were found in PSEN2, APP, MAPT, or PRNP in the patient, his parents, or his brother.

This variant was also reported in a Chinese Han man in Taiwan who had progressive memory loss starting at age 36, exaggerated emotional responses, and later developed myoclonic jerks (Lin et al., 2020). His father also had memory impairment when he died at age 42 due to an accident.

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

Neuropathology

Neuropathology was consistent with AD in the Polish family. A follow-up study showed that compared with Down's syndrome and sporadic AD patients, affected carriers of this mutation had an unusually high amyloid burden, especially in the molecular layer of the cerebellum, where a seven- and 25-fold increase was noted, respectively, compared with Down's and sporadic AD patients. The cerebellar vessel amyloid burden was also greatly increased (Wegiel et al., 1998).

Biological Effect

This mutant appears to reduce γ-processivity (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. Total secreted Aβ levels were reduced. Also, an increase in Aβ42 production in a neuronal cell line was reported earlier (Wisniewski et al., 1998). Interestingly, Liu and co-workers 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 (Liu et al., 2021; Liu et al., 2022; Apr 2022 news).

In vitro biochemical assays indicate this variant moderately reduces ε proteolysis without appreciably shifting cleavage preference (Do et al., 2023). It also appears to reduce Aβ49→Aβ46 and Aβ43→Aβ40 trimming (Devkota et al., 2024). Of note, P117L does not impair wildtype PSEN1 function when co-expressed in the same cell (Kurth et al., 2023).

Molecular dynamics simulations and fluorescence lifetime imaging microscopy suggest the mutant protein stabilizes the Aβ49/γ-secretase complex which remains stiff (Devkota et al., 2024). Although Do and colleagues reported P117L is able to adopt an active conformation, it is substantially different from that of wildtype PSEN1 (Do et al., 2023), and Devkota and colleagues reported P117L outright prevented the Aβ49/γ -secretase complex from visiting the active state. Interestingly, stalled, membrane-anchored APP/ γ-secretase complexes per se appear to be toxic to synapses (Devkota et al., 2024; Nov 2023 news).

Additional cellular functions have been reported to be impaired in cells expressing this mutant. For example, compared with cells expressing wild-type PSEN1, neurite outgrowth was inhibited in N2a cells expressing P117L, as was neurofilament assembly (Dowjat et al., 1999; Dowjat et al., 2001). BrdU incorporation studies showed that this mutation also increases cell-cycle arrest when overexpressed in HeLa cells (Janicki et al., 200 6) and decreases neuronal differentiation of murine neural progenitor cells (Eder-Colli et al., 2009). Cells expressing this variant have also been reported to have elevated levels of nuclear BRCA1 and BARD1 proteins which repair DNA double-strand breaks (Authiat et al., 2022). The authors speculate this may be a compensatory mechanism against DNA breakage caused by Aβ42.

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

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.

PS4-M

The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. P117L: The variant was reported in 3 or more unrelated patients with the same phenotype, and absent from controls.

PM1-M

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

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-S

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. P117L: At least one family with >=3 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)

Research Models

A transgenic mouse model of AD bearing this mutation has been generated, PSEN1(P117L) (line 13). These mice have decreased neurogenesis in the adult hippocampus (Wen et al., 2002; Wen et al., 2004). Knock-in P117L mice have also been created (Sato et al., 2021). These mice have been crossed with APP NL-F Knock-in mice, which carry a humanized Aβ region, resulting in mice with an accelerated rate of Aβ deposition compared with the APP NL-F Knock-in parental line.

Last Updated: 14 Feb 2024

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References

Research Models Citations

News Citations

Paper Citations

Wen PH, Shao X, Shao Z, Hof PR, Wisniewski T, Kelley K, Friedrich VL, Ho L, Pasinetti GM, Shioi J, Robakis NK, Elder GA. Overexpression of wild type but not an FAD mutant presenilin-1 promotes neurogenesis in the hippocampus of adult mice. Neurobiol Dis. 2002 Jun;10(1):8-19. PubMed.
Wen PH, Hof PR, Chen X, Gluck K, Austin G, Younkin SG, Younkin LH, DeGasperi R, Gama Sosa MA, Robakis NK, Haroutunian V, Elder GA. The presenilin-1 familial Alzheimer disease mutant P117L impairs neurogenesis in the hippocampus of adult mice. Exp Neurol. 2004 Aug;188(2):224-37. PubMed.
Sato K, Watamura N, Fujioka R, Mihira N, Sekiguchi M, Nagata K, Ohshima T, Saito T, Saido TC, Sasaguri H. A third-generation mouse model of Alzheimer's disease shows early and increased cored plaque pathology composed of wild-type human amyloid β peptide. J Biol Chem. 2021 Sep;297(3):101004. Epub 2021 Jul 27 PubMed.
Wisniewski T, Dowjat WK, Buxbaum JD, Khorkova O, Efthimiopoulos S, Kulczycki J, Lojkowska W, Wegiel J, Wisniewski HM, Frangione B. A novel Polish presenilin-1 mutation (P117L) is associated with familial Alzheimer's disease and leads to death as early as the age of 28 years. Neuroreport. 1998 Jan 26;9(2):217-21. PubMed.
Alberici A, Bonato C, Borroni B, Cotelli M, Mattioli F, Binetti G, Gennarelli M, Luca MD, Simonati A, Perani D, Rossini P, Padovani A. Dementia, delusions and seizures: storage disease or genetic AD?. Eur J Neurol. 2007 Sep;14(9):1057-9. PubMed.
Wegiel J, Wisniewski HM, Kuchna I, Tarnawski M, Badmajew E, Popovitch E, Kulczycki J, Dowjat WK, Wisniewski T. Cell-type-specific enhancement of amyloid-beta deposition in a novel presenilin-1 mutation (P117L). J Neuropathol Exp Neurol. 1998 Sep;57(9):831-8. 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.
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.
Do HN, Devkota S, Bhattarai A, Wolfe MS, Miao Y. Effects of presenilin-1 familial Alzheimer's disease mutations on γ-secretase activation for cleavage of amyloid precursor protein. Commun Biol. 2023 Feb 14;6(1):174. PubMed.
Devkota S, Zhou R, Nagarajan V, Maesako M, Do H, Noorani A, Overmeyer C, Bhattarai S, Douglas JT, Saraf A, Miao Y, Ackley BD, Shi Y, Wolfe MS. Familial Alzheimer mutations stabilize synaptotoxic γ-secretase-substrate complexes. Cell Rep. 2024 Feb 27;43(2):113761. Epub 2024 Feb 13 PubMed.
Kurth V, Ogorek I, Münch C, Lopez-Rios J, Ousson S, Lehmann S, Nieweg K, Roebroek AJ, Pietrzik CU, Beher D, Weggen S. Pathogenic Aβ production by heterozygous PSEN1 mutations is intrinsic to the mutant protein and not mediated by conformational hindrance of wild-type PSEN1. J Biol Chem. 2023 Aug;299(8):104997. Epub 2023 Jun 30 PubMed.
Dowjat WK, Wisniewski T, Efthimiopoulos S, Wisniewski HM. Inhibition of neurite outgrowth by familial Alzheimer's disease-linked presenilin-1 mutations. Neurosci Lett. 1999 May 28;267(2):141-4. PubMed.
Dowjat WK, WISNIEWSKI H, Wisniewski T. Alzheimer's disease presenilin-1 expression modulates the assembly of neurofilaments. Neuroscience. 2001;103(1):1-8. PubMed.
Janicki SM, Stabler SM, Monteiro MJ. Familial Alzheimer's disease presenilin-1 mutants potentiate cell cycle arrest. Neurobiol Aging. 2000 Nov-Dec;21(6):829-36. PubMed.
Eder-Colli L, Abad-Estarlich N, Pannetier C, Vallet PG, Walzer C, Elder GA, Robakis NK, Bouras C, Savioz A. The presenilin-1 familial Alzheimer's disease mutation P117L decreases neuronal differentiation of embryonic murine neural progenitor cells. Brain Res Bull. 2009 Oct 28;80(4-5):296-301. PubMed.
Authiat MM, Gruz-Gibelli E, Colas J, Bianchi E, Garcia-Arauzo M, Marin P, Herrmann FR, Savioz A. Preferential Involvement of BRCA1/BARD1, Not Tip60/Fe65, in DNA Double-Strand Break Repair in Presenilin-1 P117L Alzheimer Models. Neural Plast. 2022;2022:3172861. Epub 2022 Feb 21 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 P117L

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