Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PS4, PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73659441 T>C
dbSNP ID: rs63751039
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: ATT to ACT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This mutation was first identified in a Japanese family known as OS-2, which was affected by early onset Alzheimer’s disease (Kamino et al., 1996). The reported pedigree shows four affected individuals over two generations. The mean age of onset in this family was 45.0 ± 4.24 (range: 42-48). Further clinical details were not reported. The mutation was found in one affected family member by direct sequencing. Segregation with disease could not be determined due to lack of DNA from other family members.

The mutation was also reported in two additional unrelated individuals and a family suffering from early onset dementia. One was a French individual diagnosed with AD whose symptoms started at age 42 and who developed seizures at age 46 (Zarea et al. 2016). Another was a Chinese Han woman whose memory began declining at age 40 and who developed irritability as the impairment progressed (Han et al., 2020). Her mother and elder brother had similar symptoms, but neither were available for genotyping. Moreover, a report from the Chinese Familial Alzheimer’s Disease Network described a family with four affected carriers, three diagnosed with AD and one with mild cognitive impairment (Jia et al., 2020). All had ages at onset in their 40s.

The variant was absent from the gnomAD variant database (Han et al., 2020).

Neuropathology

Unknown.

Biological Effect

This mutant was initially reported to reduce de novo generation of Aβ peptides, particularly Aβ40 relative to Aβ42, as revealed by assays monitoring cleavage of APP C99 in lysates from PSEN-deficient mouse embryonic fibroblasts stably expressing either wild-type or the I213T PSEN1 mutant (Shimojo et al., 2008). This alteration resulted in an increased Aβ42/Aβ40 ratio. In addition, mutant lysates had increased levels of longer Aβ species, including Aβ43, Aβ45, and Aβ46+. The results were confirmed in I213T knock-in mouse brains. Consistent with these findings, Chávez-Gutiérrez and colleagues reported low levels of Aβ40 and Aβ38 and high levels of long Aβ species (>Aβ42) using both in vitro and cell-based assays (Chávez-Gutiérrez et al., 2012). Moreover, they found Aβ38/Aβ42 and Aβ40/Aβ43 ratios were drastically reduced indicating impairment of the fourth γ-secretase cleavage in the two Aβ production lines that sequentially digest Aβ49 and Aβ48 into shorter peptides. The mutant does not appear to affect Notch processing, however. A subsequent cell-based study also showed decreased production of short peptides, Aβ38 and Aβ40, and increased production of longer peptides, Aβ42 and Aβ43 (Kakuda et al., 2021). The authors suggested some PSEN1 mutations may cause a switch in the stepwise processing pathway that leads to Aβ43 production, however, I213T produced relatively low levels of a peptide indicating this switch, VIVIT, as compared with controls.

A cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates 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).

This mutant also appears to affect functions beyond APP processing. In cortical neuronal cultures from a knockin mouse expressing one or two I213T alleles, the mutant protein was reported to inhibit the neuroprotective functions of trophic factors eB1 and BDNF following glutamate excitotoxicity (Al Rahim et al., 2020). The effect appeared to be dominant-negative, with mutant PSEN1 altering the stability of complexes formed between PSEN1, the glutamate NMDA receptor, and trophic factor receptors. Yet another function affected by this mutation appears to be angiogenesis. In brains from knockin mice, the ability of cortical endothelial cells to sprout and form new blood vessels after ischemia was decreased, apparently due to reduced γ-secretase cleavage of the angiogenic peptide ephrinB2 (Yoon et al., 2020).

Several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve) predicted this variant is damaging (Xiao et al., 2021, Han et al., 2020).

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. I213T: 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. I213T: Variant is in a mutational hot spot; 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.

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

Knock-in mice with this mutation have been created and shown to accumulate Aβ42 in a gene-dosage-dependent manner (Nakano et al., 1999).

Last Updated: 04 Mar 2022

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References

News Citations

Paper Citations

Nakano Y, Kondoh G, Kudo T, Imaizumi K, Kato M, Miyazaki JI, Tohyama M, Takeda J, Takeda M. Accumulation of murine amyloidbeta42 in a gene-dosage-dependent manner in PS1 'knock-in' mice. Eur J Neurosci. 1999 Jul;11(7):2577-81. PubMed.
Kamino K, Sato S, Sakaki Y, Yoshiiwa A, Nishiwaki Y, Takeda M, Tanabe H, Nishimura T, Ii K, St George-Hyslop PH, Miki T, Ogihara T. Three different mutations of presenilin 1 gene in early-onset Alzheimer's disease families. Neurosci Lett. 1996 Apr 26;208(3):195-8. PubMed.
Zarea A, Charbonnier C, Rovelet-Lecrux A, Nicolas G, Rousseau S, Borden A, Pariente J, Le Ber I, Pasquier F, Formaglio M, Martinaud O, Rollin-Sillaire A, Sarazin M, Croisile B, Boutoleau-Bretonnière C, Ceccaldi M, Gabelle A, Chamard L, Blanc F, Sellal F, Paquet C, Campion D, Hannequin D, Wallon D, PHRC GMAJ Collaborators. Seizures in dominantly inherited Alzheimer disease. Neurology. 2016 Aug 30;87(9):912-9. Epub 2016 Jul 27 PubMed.
Han LH, Xue YY, Zheng YC, Li XY, Lin RR, Wu ZY, Tao QQ. Genetic Analysis of Chinese Patients with Early-Onset Dementia Using Next-Generation Sequencing. Clin Interv Aging. 2020;15:1831-1839. Epub 2020 Oct 2 PubMed.
Jia L, Fu Y, Shen L, Zhang H, Zhu M, Qiu Q, Wang Q, Yan X, Kong C, Hao J, Wei C, Tang Y, Qin W, Li Y, Wang F, Guo D, Zhou A, Zuo X, Yu Y, Li D, Zhao L, Jin H, Jia J. PSEN1, PSEN2, and APP mutations in 404 Chinese pedigrees with familial Alzheimer's disease. Alzheimers Dement. 2020 Jan;16(1):178-191. PubMed.
Shimojo M, Sahara N, Mizoroki T, Funamoto S, Morishima-Kawashima M, Kudo T, Takeda M, Ihara Y, Ichinose H, Takashima A. Enzymatic characteristics of I213T mutant presenilin-1/gamma-secretase in cell models and knock-in mouse brains: familial Alzheimer disease-linked mutation impairs gamma-site cleavage of amyloid precursor protein C-terminal fragment beta. J Biol Chem. 2008 Jun 13;283(24):16488-96. Epub 2008 Apr 21 PubMed.
Chávez-Gutiérrez L, Bammens L, Benilova I, Vandersteen A, Benurwar M, Borgers M, Lismont S, Zhou L, Van Cleynenbreugel S, Esselmann H, Wiltfang J, Serneels L, Karran E, Gijsen H, Schymkowitz J, Rousseau F, Broersen K, De Strooper B. The mechanism of γ-Secretase dysfunction in familial Alzheimer disease. EMBO J. 2012 May 16;31(10):2261-74. Epub 2012 Apr 13 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.
Al Rahim M, Yoon Y, Dimovasili C, Shao Z, Huang Q, Zhang E, Kezunovic N, Chen L, Schaffner A, Huntley GW, Ubarretxena-Belandia I, Georgakopoulos A, Robakis NK. Presenilin1 familial Alzheimer disease mutants inactivate EFNB1- and BDNF-dependent neuroprotection against excitotoxicity by affecting neuroprotective complexes of N-methyl-d-aspartate receptor. Brain Commun. 2020;2(2):fcaa100. Epub 2020 Jul 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 I213T

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