Mutations

PSEN1 P117L

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73640285 C>T
dbSNP ID: rs63749805
Coding/Non-Coding: Coding
Mutation Type: Point, 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.

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. 

Moreover, several cellular functions have been reported to be impaired in cells expressing this mutant. 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., 2006) and decreases neuronal differentiation of murine neural progenitor cells (Eder-Colli et al., 2009).

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)

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).

Last Updated: 30 Jul 2021

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References

Research Models Citations

  1. PSEN1(P117L) (line 13)

Paper Citations

  1. . 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.
  2. . 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.
  3. . 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.
  4. . Dementia, delusions and seizures: storage disease or genetic AD?. Eur J Neurol. 2007 Sep;14(9):1057-9. PubMed.
  5. . 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.
  6. . 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 Jan-Jun;296:100393. Epub 2021 Feb 8 PubMed.
  7. . Inhibition of neurite outgrowth by familial Alzheimer's disease-linked presenilin-1 mutations. Neurosci Lett. 1999 May 28;267(2):141-4. PubMed.
  8. . Alzheimer's disease presenilin-1 expression modulates the assembly of neurofilaments. Neuroscience. 2001;103(1):1-8. PubMed.
  9. . Familial Alzheimer's disease presenilin-1 mutants potentiate cell cycle arrest. Neurobiol Aging. 2000 Nov-Dec;21(6):829-36. PubMed.
  10. . 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.
  11. . 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.

External Citations

  1. gnomAD v2.1.1

Further Reading

Papers

  1. . [Familial Alzheimer's disease connected with mutation in presenilin gene 1 (P117L)]. Neurol Neurochir Pol. 2001 Mar-Apr;35(2):213-24. PubMed.
  2. . Small cerebral vessel disease in familial amyloid and non-amyloid angiopathies: FAD-PS-1 (P117L) mutation and CADASIL. Immunohistochemical and ultrastructural studies. Folia Neuropathol. 2007;45(4):192-204. PubMed.

Protein Diagram

Primary Papers

  1. . 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.

Other mutations at this position

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