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):Chr14:73192793 T>C
Position: (GRCh37/hg19):Chr14:73659501 T>C
dbSNP ID: rs63751024
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: ATG to ACG
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7
Research Models: 1

Findings

This mutation was first reported in an Australian pedigree known as PERTH1, which had familial early onset AD (Kwok et al., 1997). The family had four affected individuals over three generations. The mutation segregated with disease in this family; it was present in all three living affected family members and absent in three unaffected members. Affected family members developed symptoms at 33, 34, and 38 years; age at onset was unknown in one individual.

M233T was also found in three French kindreds, the first with five affected individuals over three generations named ALZ 079. Age of onset in this family ranged from 38 to 45 years and segregation with disease was confirmed (Campion et al., 1999). A second French kindred, known as ALZ 202, consisted of three affected individuals who met NINCDS-ADRDA criteria for probable or definite AD. Age at onset in this family was 38 to 40 years (Raux et al., 2005). Lastly, a family identified as EXT 1201 had an age at onset between 44 and 45 years and disease duration of two to four years (Lanoiselée et al., 2017). Segregation with disease was not assessed.

This mutation has also been found in two Korean women with early onset AD, but no known family history of dementia (Park et al., 2008; Park et al., 2020). The first reported case experienced symptom onset at age 34 (Park et al., 2008). Her disease progressed rapidly; at age 36 she scored 20/30 on the Korean Mini-Mental State Examination; two years later she scored 4/30. Symptoms included memory and visuospatial impairments, apraxia, aphasia, and optic ataxia. The other Korean carrier began experiencing memory impairment and depression at age 29 (Park et al., 2020).

In addition, the M233T mutation was found in a Caucasian man of Spanish or Portuguese ancestry. He first presented with clinical symptoms at age 35 and died at the age of 42. Presenting symptoms were atypical for AD, including prominent behavioral symptoms (depression/apathy and aggressiveness) and extrapyramidal signs such as dysarthria, left hand apraxia, face and foot dystonia, and pyramidal signs (Babinski). He later developed myoclonus and tonic-clonic seizures. The family history was unclear (Guerreiro et al., 2010).

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

Neuropathology

Neuropathology consistent with AD was reported in at least one case (Kwok et al., 1997). In another case, cerebrospinal fluid levels of Aβ42, tau, and phospho-tau were consistent with AD (Lanoiselée et al., 2017).

Moreover, in yet another carrier, FBB-PET revealed amyloid positivity and MRI showed bilateral parietal atrophy (Park et al., 2020), and in another, MRI revealed parietotemporal and hippocampal atrophy (Guerreiro et al., 2010). In addition, FDG-PET showed hypometabolism that was diffuse throughout the brain in one case (Park et al., 2008), and more evident in temporoparietal areas in another (Park et al., 2020).

Biological Effect

Cell-based assays have shown this mutant alters the production of several Aβ peptides, most notably increasing the Aβ42/40 ratio and decreasing the Aβ37/40 ratio (Liu et al., 2022, Apr 2022 news). Both ratios, particularly the latter, were shown to be predictive of AD. Moreover, a follow-up study reported in a preprint, combined the Aβ (37 + 38 + 40) / (42 + 43) ratio with the Aβ42/Aβ40 ratio to yield a composite measure which reflects γ-secretase function as a percentage of wildtype activity (Schulz et al., 2023). This score (28.77 for M233T) was strongly associated, not only with age at onset, but with biomarker and cognitive trajectories.

Interestingly, while many AD-associated PSEN1 mutations result in increased levels of Aβ42 and longer Aβ peptides, with decreased levels of shorter peptides, M233T appears to deviate somewhat from this pattern. CHO cells co-expressing APP and mutant PSEN1 boosted production of Aβ42, Aβ48, and Aβ39, while decreasing levels of Aβ38, Aβ40, Aβ43, and Aβ46 (Qi et al., 2003; Sato et al., 2003; Qi-Takahara et al., 2005; Kakuda et al., 2021). Analyses of the changes in peptide ratios and in the small peptides released during APP processing provided greater insight into these alterations (Kakuda et al., 2021). Of note, the Aβ38/Aβ40 ratio in cells expressing this mutation was greater than that of cells expressing other familial AD mutations or wildype PSEN1.

An in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate revealed increased Aβ42 and decreased Aβ40 production, yielding an approximately 10-fold increase in the Aβ42/Aβ40 ratio (Sun et al., 2017).

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). As described in another cryo-EM study, substitution of methionine with threonine, a smaller hydrophilic residue, is expected to reduce the strength of the PSEN1-APP hydrophobic interaction (Guo et al., 2024; Jun 2024 news). Based on molecular dynamics simulations, the residue has been implicated in the formation of an internal docking site that stabilizes substrate binding (Chen and Zacharias, 2022).

This residue is conserved between PSEN1 and PSEN2. Pathogenic mutations have been reported in the homologous PSEN2 residue (M239I and M239V).

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 (Park et al., 2020; 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. M233T: 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. M233T: 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-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. M233T: At least one family with >=3 affected carriers and >=1 unaffected noncarriers and cosegregation demonstrated in >1 family.

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

This mutation has been introduced into mouse models of disease, including the APP751SL/PS1 KI double mutant, which also expresses APP with the London (V717I) and Swedish (K670N/M671L) mutations.

Last Updated: 13 Jun 2024

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References

Research Models Citations

News Citations

Paper Citations

Kwok JB, Taddei K, Hallupp M, Fisher C, Brooks WS, Broe GA, Hardy J, Fulham MJ, Nicholson GA, Stell R, St George Hyslop PH, Fraser PE, Kakulas B, Clarnette R, Relkin N, Gandy SE, Schofield PR, Martins RN. Two novel (M233T and R278T) presenilin-1 mutations in early-onset Alzheimer's disease pedigrees and preliminary evidence for association of presenilin-1 mutations with a novel phenotype. Neuroreport. 1997 Apr 14;8(6):1537-42. PubMed.
Campion D, Dumanchin C, Hannequin D, Dubois B, Belliard S, Puel M, Thomas-Anterion C, Michon A, Martin C, Charbonnier F, Raux G, Camuzat A, Penet C, Mesnage V, Martinez M, Clerget-Darpoux F, Brice A, Frebourg T. Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am J Hum Genet. 1999 Sep;65(3):664-70. PubMed.
Raux G, Guyant-Maréchal L, Martin C, Bou J, Penet C, Brice A, Hannequin D, Frebourg T, Campion D. Molecular diagnosis of autosomal dominant early onset Alzheimer's disease: an update. J Med Genet. 2005 Oct;42(10):793-5. Epub 2005 Jul 20 PubMed.
Lanoiselée HM, Nicolas G, Wallon D, Rovelet-Lecrux A, Lacour M, Rousseau S, Richard AC, Pasquier F, Rollin-Sillaire A, Martinaud O, Quillard-Muraine M, de la Sayette V, Boutoleau-Bretonniere C, Etcharry-Bouyx F, Chauviré V, Sarazin M, le Ber I, Epelbaum S, Jonveaux T, Rouaud O, Ceccaldi M, Félician O, Godefroy O, Formaglio M, Croisile B, Auriacombe S, Chamard L, Vincent JL, Sauvée M, Marelli-Tosi C, Gabelle A, Ozsancak C, Pariente J, Paquet C, Hannequin D, Campion D, collaborators of the CNR-MAJ project. APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases. PLoS Med. 2017 Mar;14(3):e1002270. Epub 2017 Mar 28 PubMed.
Park HK, Na DL, Lee JH, Kim JW, Ki CS. Identification of PSEN1 and APP gene mutations in Korean patients with early-onset Alzheimer's disease. J Korean Med Sci. 2008 Apr;23(2):213-7. PubMed.
Park JE, Kim HJ, Kim YE, Jang H, Cho SH, Kim SJ, Na DL, Won HH, Ki CS, Seo SW. Analysis of dementia-related gene variants in APOE ε4 noncarrying Korean patients with early-onset Alzheimer's disease. Neurobiol Aging. 2020 Jan;85:155.e5-155.e8. Epub 2019 May 22 PubMed.
Guerreiro RJ, Baquero M, Blesa R, Boada M, Brás JM, Bullido MJ, Calado A, Crook R, Ferreira C, Frank A, Gómez-Isla T, Hernández I, Lleó A, Machado A, Martínez-Lage P, Masdeu J, Molina-Porcel L, Molinuevo JL, Pastor P, Pérez-Tur J, Relvas R, Oliveira CR, Ribeiro MH, Rogaeva E, Sa A, Samaranch L, Sánchez-Valle R, Santana I, Tàrraga L, Valdivieso F, Singleton A, Hardy J, Clarimón J. Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP. Neurobiol Aging. 2010 May;31(5):725-31. Epub 2008 Jul 30 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.
Schultz S, Liu L, Schultz A, Fitzpatrick C, Levin R, Bellier J-P, Shirzadi Z, Mathurin N, Chen C, Benzinger T, Day G, Farlow M, Gordon B, Hassenstab J, Jack C, Jucker M, Karch C, Lee J, Levin J, Perrin R, Schofield P, Xiong C, Johnson K, McDade E, Bateman R, Sperling R, Selkoe D, Chhatwal J, theDominantlyInheritedAlzheimer'sNetworkInvestigators. Functional variations in gamma-secretase activity are critical determinants of the clinical, biomarker, and cognitive progression of autosomal dominant Alzheimer's disease. 2023 Jul 25 10.1101/2023.07.04.547688 (version 2) bioRxiv.
Qi Y, Morishima-Kawashima M, Sato T, Mitsumori R, Ihara Y. Distinct mechanisms by mutant presenilin 1 and 2 leading to increased intracellular levels of amyloid beta-protein 42 in Chinese hamster ovary cells. Biochemistry. 2003 Feb 4;42(4):1042-52. PubMed.
Sato T, Dohmae N, Qi Y, Kakuda N, Misonou H, Mitsumori R, Maruyama H, Koo EH, Haass C, Takio K, Morishima-Kawashima M, Ishiura S, Ihara Y. Potential link between amyloid beta-protein 42 and C-terminal fragment gamma 49-99 of beta-amyloid precursor protein. J Biol Chem. 2003 Jul 4;278(27):24294-301. PubMed.
Qi-Takahara Y, Morishima-Kawashima M, Tanimura Y, Dolios G, Hirotani N, Horikoshi Y, Kametani F, Maeda M, Saido TC, Wang R, Ihara Y. Longer forms of amyloid beta protein: implications for the mechanism of intramembrane cleavage by gamma-secretase. J Neurosci. 2005 Jan 12;25(2):436-45. 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.
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.
Guo X, Li H, Yan C, Lei J, Zhou R, Shi Y. Molecular mechanism of substrate recognition and cleavage by human γ-secretase. Science. 2024 Jun 7;384(6700):1091-1095. Epub 2024 Jun 6 PubMed.
Chen SY, Zacharias M. An internal docking site stabilizes substrate binding to γ-secretase: Analysis by molecular dynamics simulations. Biophys J. 2022 Jun 21;121(12):2330-2344. Epub 2022 May 20 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 M233T

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