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):Chr14:73192792 A>C
Position: (GRCh37/hg19):Chr14:73659500 A>C
dbSNP ID: rs63751287
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: ATG to CTG
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This mutation was first detected in an individual from Spain who met NINCDS-ADRDA criteria for Alzheimer’s disease (McKhann et al., 1984). Symptom onset occurred at age 46; further clinical details were not reported. The patient did not have a family history of dementia, and segregation with disease could not be assessed (Aldudo et al., 1999).

This mutation was subsequently found in another individual. Clinical details were not reported (Rogaeva et al., 2001).

More recently, this mutation was found in a Han Chinese family with a history of early-onset AD (Jiang et al., 2014). The reported pedigree shows five affected individuals over two generations: four siblings and their mother. The proband was a 38-year-old woman with a one-year-history of memory loss. Disease in this family was characterized by early onset and rapid progression, with onset ranging from 37 to 44 years of age. Epilepsy was also common, as was paralysis and psychiatric symptoms. The mutation appeared to segregate with disease in this family: It was detected in two affected individuals but absent in the proband’s father who was unaffected at age 76.

The mutation was also found in a Spanish family from the same city as the family in which the mutation was first identified, but no relationship could be established between the two (Navarro et al., 2015). Three affected members were examined and found to carry the mutation. Two presented with memory loss typical of AD, and the third developed prominent cortico-basal syndrome with severe neuropsychiatric and behavioral disruptions. The pattern of inheritance was consistent with an autosomal dominant mutation. Affected family members typically had memory problems at presentation, and occasionally developed myoclonus, seizures, or aphasia in advanced stages of disease.

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

Neuropathology

In the individual who developed corticobasal syndrome, neuropathology was consistent with AD, and, in a biopsy, no signs of frontotemporal or corticobasal degeneration were observed (Navarro et al., 2015). Prior to autopsy, MRI revealed marked asymmetric (right greater than left) cortical atrophy and mild‐to‐moderate subcortical and periventricular white matter alterations. Ventricular enlargement was particularly robust in the right occipital horn. In addition, right frontotemporal hypometabolism was identified using SPECT imaging. In another patient from this family, MRI showed symmetrical frontal and temporal cortical atrophy, and SPECT imaging revealed bilateral parietal and temporal hypoperfusion, with mild anterior frontal involvement. In yet another family member, an MRI scan yielded normal results, but SPECT images showed bilateral temporo‐parietal‐occipital perfusion defects that were more marked on the left, including left posterior frontal involvement. In the Han Chinese family, imaging results indicated global cerebral atrophy (Jiang et al., 2014).

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.

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).

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).

Five other pathogenic mutations have been described at codon 233, and a pathogenic mutation (M239V), has been documented at the homologous codon in PSEN2.

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. M233L (A>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. M233L (A>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. M233L (A>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)

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.

Last Updated: 07 Mar 2022

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References

News Citations

Paper Citations

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.
McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology. 1984 Jul;34(7):939-44. PubMed.
Aldudo J, Bullido MJ, Valdivieso F. DGGE method for the mutational analysis of the coding and proximal promoter regions of the Alzheimer's disease presenilin-1 gene: two novel mutations. Hum Mutat. 1999;14(5):433-9. PubMed.
Rogaeva EA, Fafel KC, Song YQ, Medeiros H, Sato C, Liang Y, Richard E, Rogaev EI, Frommelt P, Sadovnick AD, Meschino W, Rockwood K, Boss MA, Mayeux R, St George-Hyslop P. Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.
Jiang HY, Li GD, Dai SX, Bi R, Zhang DF, Li ZF, Xu XF, Zhou TC, Yu L, Yao YG. Identification of PSEN1 mutations p.M233L and p.R352C in Han Chinese families with early-onset familial Alzheimer's disease. Neurobiol Aging. 2015 Mar;36(3):1602.e3-6. Epub 2014 Dec 18 PubMed.
Navarro E, De Andrés C, Guerrero C, Giménez-Roldán S. Corticobasal Syndrome in a Family with Early-Onset Alzheimer's Disease Linked to a Presenilin-1 Gene Mutation. Mov Disord Clin Pract. 2015 Dec;2(4):388-394. Epub 2015 Jul 25 PubMed.
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.
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.
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.
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 M233L (A>C)

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