Overview

Pathogenicity: Frontotemporal Dementia : Not Classified
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73192792 A>T
Position: (GRCh37/hg19):Chr14:73659500 A>T
dbSNP ID: rs63751287
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: ATG to TTG
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This mutation was found in a woman who experienced personality changes characteristic of fronto-temporal dementia starting at age 39 (Mendez et al., 2006). Symptoms included alterations in social behavior, abnormal personality regulation, emotional blunting, and poor insight. She also experienced a decline in personal hygiene, rigidity, compulsions, and changes in dietary/oral behaviors.

Several families carrying the related M233L (A>C) have been described. In these cases, symptoms and neuropathology have been reported as typical of AD, although one individual developed corticobasal syndrome.

This variant was absent from the gnomAD variant database (gnomAD v2.1.1, July 2021).

Neuropathology
Neuropathological data are unavailable, but SPECT imaging of this single case revealed hypoperfusion in posterior parietal areas, and a subsequent PET scan showed hypometabolism in prefrontal, parietal, and temporal cortices. MRI revealed global cerebral atrophy. 

Biological Effect
An in vitro assay using an M233L mutant (nucleotide change unspecified) and APP C99 as a substrate, revealed increased production of Aβ42, a moderate decrease in Aβ40 production, and a corresponding increase in the Aβ42/Aβ40 ratio (Bai et al., 2015; Sun et al., 2017). An elevated Aβ42/Aβ40 ratio was also reported in neurons derived from induced pluripotent stem cells (iPSCs) and in transfected human embryonic kidney cells, which showed elevated levels of Aβ42 and Aβ43 in culture supernatants (Kwart et al., 2019, Aug 2019 news, Kakuda et al., 2021). M233L was also shown to promote the accumulation of APP β-C-terminal fragments which disrupt endosomes.

Multiple 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).

Several other pathogenic mutations have been described at codon 233, and a pathogenic mutation (M239V), has been documented at the homologous codon in PSEN2. A cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates that, in wild-type PSEN1, 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).

Research Models

An induced pluripotent cell (iPSC) line carrying this amino acid substitution (nucleotide change unspecified) has been created using CRISPR technology (Kwart et al., 2019). It is part of a collection of isogenic iPSCs carrying familial AD mutations.

Comments

1. • Takaomi Saido
     RIKEN Center for Brain Science
   • Posted: 09 Sep 2006
   • Paper: Frontotemporal dementia-like phenotypes associated with presenilin-1 mutations.

   This paper adds another example for the possible presence of a loss-of-function phenotype of PS mutations. In my view, (relative) elevation of Aβ42 is a gain-of-function phenotype commonly shared by most of the mutations, although the mechanism behind it may be a kind of loss-of-function type, that is, downregulation of Aβ40 generation. The PS mutations described in this paper and elsewhere, some of which do not even produce all the AD pathologies, seem to belong to a subclass of the entire set of pathogenic PS mutations.

   View all comments by Takaomi Saido

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References

News Citations

1. Familial AD Mutations, β-CTF, Spell Trouble for Endosomes 16 Aug 2019
2. CryoEM γ-Secretase Structures Nail APP, Notch Binding 11 Jan 2019

Paper Citations

1. Kwart D, Gregg A, Scheckel C, Murphy EA, Paquet D, Duffield M, Fak J, Olsen O, Darnell RB, Tessier-Lavigne M. A Large Panel of Isogenic APP and PSEN1 Mutant Human iPSC Neurons Reveals Shared Endosomal Abnormalities Mediated by APP β-CTFs, Not Aβ. Neuron. 2019 Oct 23;104(2):256-270.e5. Epub 2019 Aug 12 PubMed.
2. Mendez MF, McMurtray A. Frontotemporal dementia-like phenotypes associated with presenilin-1 mutations. Am J Alzheimers Dis Other Demen. 2006 Aug-Sep;21(4):281-6. PubMed.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.

Other Citations

1. M233L (A>C)

External Citations

1. gnomAD v2.1.1

Further Reading