Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM2, PP1, PP3, BS2
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr1:226885603 A>T
Position: (GRCh37/hg19):Chr1:227073304 A>T
dbSNP ID: rs63750215
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Splicing Alteration; Substitution
Expected Protein Consequence: Deletion; Missense
Codon Change: AAC to ATC
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 6
Research Models: 5

Findings

This was the first pathogenic mutation described in PSEN2; it was discovered in conjunction with the cloning of the gene (Levy-Lahad et al., 1995; Rogaev et al., 1995). It is also the most common PSEN2 mutation worldwide, with more than 11 families identified. The origin of at least some of these families has been traced to a region along the Volga River in Russia (Bird et al., 1988). 

The clinical features associated with the N141I mutation were summarized in a comprehensive review of PSEN2 mutations (Jayadev et al., 2010). Clinical data for 101 affected individuals in 11 families was reported. The number of affected individuals per family varied from two to 26. The mean age of onset was 53.7 years (range: 39 to 75 years). The mean age at death was 64.2 years, and the mean disease duration was 10.6 years. In these families, disease onset was characterized by memory problems and/or other cognitive deficits. The disease course tended to be slower than is typical of other familial AD mutations, especially those in PSEN1. Pyramidal signs or parkinsonian symptoms were not common early in the disease. Of the 64 AD patients with detailed medical records, 31 percent had one or more seizures and 33 percent had hallucinations, delusions, or other psychotic features.

Although the clinical penetrance of this mutation is very high (approximately 95 percent), there are a few isolated reports of decreased penetrance in which individuals reached the ninth decade without cognitive decline. One mutation carrier in the HB family was cognitively intact at age 80 when he died from cancer. Another presumed N141I carrier from the H family was similarly dementia-free when he died at age 89, also from cancer. No carriers have been reported in the gnomAD variant database (v2.1.1, Nov 2021).

Two additional carriers of the Volga German mutation were identified in Germany (Blauwendraat et al., 2015). Haplotype analysis suggested that they are part of the larger Volga German kindred. One mutation carrier developed progressive dementia at age 51 and died at age 61 following a disease characterized by memory loss, rigidity, and generalized tonic-clonic seizures. The other mutation carrier in the study, not known to be related, developed language impairment and personality changes at age 56, including word-finding difficulties and a blunt affect. She was originally diagnosed with the FTD subtype, progressive nonfluent aphasia. However, her prominent memory decline prompted a revised diagnosis of logopenic variant of primary progressive aphasia due to AD. She later developed tonic-clonic seizures. Her father had died from AD at age 60, and her sister was similarly affected, with onset at age 55. Of note, two Argentinian families of German ancestry were also reported in the literature with a mean age at onset of 53 years (Llibre-Guerra et al., 2021).

On a historical note, Alois Alzheimer’s famous patient, Auguste Deter (Auguste D.), lived in the same region of Germany as a modern-day family with the N141I mutation. This raised the possibility that she too may have carried this mutation (Yu et al., 2010); however, this was later shown not to be the case (Müller et al., 2011; Rupp et al., 2014).

Neuropathology

In general, postmortem analysis of affected N141I mutation carriers has shown extensive amyloid plaques and neurofibrillary tangles, with 17 of 18 brain samples receiving a Braak score of V or VI and a CERAD plaque score of C, thus fulfilling pathologic criteria for definite Alzheimer’s disease (Braak and Braak, 1991; Mirra et al., 1991). Inclusions of α-synuclein were common in the amygdala (14/18, 78 percent) but much less common in the substantia nigra (7/16, 44 percent) and the neocortex (3/17, 18 percent) (see also Leverenz et al., 2006). TDP-43 pathology was not commonly observed (3/13, 23 percent). Hippocampal sclerosis was similarly rare (3/13, 23 percent). For additional details, see Jayadev et al., 2010.

Biological Effect

This variant has been associated with multiple biological effects. Consistent with the localization of PSEN2 in endolysosomal vesicles (Jun 2016 news), in vivo effects on hippocampal plasticity and synapses tied to endolysosomal deficits have been reported (Dec 2024 news; Perdok et al., 2024). In this study, mice carrying N141I were crossed with a knock-in AD mouse model carrying three pathogenic APP mutations (APPNL-G-F). The presence of N141I resulted in earlier and more dense plaque deposition, increased dystrophic neurites, early hyperactivity, and more severe memory loss. These phenotypes correlated with increased PSEN2 expression, reduced long-term potentiation, and pre- and post-synaptic alterations in the hippocampal mossy fiber-CA3 pyramidal cell pathway. Potentially underlying the synaptic alterations, the researchers identified deficits in endolysosomal functions, including increased basal calcium levels in late endosomes and lysosomes, reduced TRPML1-dependent calcium release and exocytosis, and an accumulation of LC3+ autophagosomes. Moreover, the mice exhibited increased levels of APP C-terminal fragments which have been connected to endolysosomal alterations in AD pathology.

Several studies have probed the effects of N141I on proteolytic activity. Although when transfected into fibroblasts lacking endogenous PSEN1 or PSEN2, the N141I mutation did not affect steady-state levels of the proteolytic products PSEN2-CTF and PSEN2-NTF compared with wild-type PSEN2 (Walker et al., 2005), the mutation does appear to impair γ-secretase activity. When co-transfected with APP carrying the Swedish mutation, it produced elevated levels of Aβ42 and increased the Aβ42/Aβ40 ratio (Walker et al., 2005). In addition, in three-dimensional brain organoids generated from patient-derived induced pluripotent stem cells, an increased Aβ42/Aβ40 ratio was observed, as well as asynchronous calcium transients and neuronal hyperactivity (Yin et al., 2021).

Altered γ-secretase activity was also reported in microglia of transgenic mice expressing one copy of N141I, one copy of wildtype PSEN2, and two copies of wildtype PSEN1 (Fung et al., 2020). Interestingly, these microglia also released higher levels of inflammatory cytokines, had increased NFκB activity, and internalized Aβ more readily than microglia from control mice. In vivo, IL-6 and TREM2 expression were elevated in brain and microglial activated morphology was observed in the absence of inflammatory stimuli. Moreover, intraperitoneal injection of LPS, an inflammation trigger, increased gene expression of inflammatory genes to a greater extent than in control mice. In the APPNL-G-F mice carrying N141I, however, microglial recruitment to plaques was delayed (Perdok et al., in preparation; Perdok et al., 2024).

Studying the effects of this mutation in heterozygous knock-in mice, another group reported selective overproduction of cytokines controlled by circadian clock genes (Nam et al., 2022). This alteration appeared to be mediated by epigenetic repression of REV-ERBα, a transcriptional factor involved in the circadian control of innate immunity. The knockin mice had an exaggerated proinflammatory response to a low dose of LPS and concomitant memory impairment.

Alterations in other biological processes have also been reported. Experiments with patient-derived fibroblasts suggested this variant increases tethering of mitochondria to the endoplasmic reticulum by interfering with the activity of mitofusin 2, and favoring calcium crosstalk between the organelles (Filadi et al., 2016, Rossini et al., 2021).

Interestingly, altered splicing has also been associated with this mutation. Analyzing mRNA from two carriers revealed that nearly 10 percent of their mutation-containing transcripts lacked exon 6 (Course et al., 2023). This leads to a predicted premature termination codon, suggesting partial loss-of-function. N141 is in the middle of exon 6, but how its substitution to an isoleucine promotes alternative splicing remains unknown. The position is not within an established binding site for HMGA1A, which can promote exon 6 skipping.

Also, less than half of PSEN2 transcripts contained the N141I mutation suggesting decreased stability, possible via nonsense-mediated decay (Course et al., 2023).

This variant's PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, Nov 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.

Research Models

Several induced pluripotent stem cell (iPSC) lines have been created using fibroblasts isolated from N141I mutation carriers (Murti et al., 2020, Raska et al., 2021, Marei et al., 2021, Yin et al., 2021). Of note, one of these lines was used to create cells in which the mutation was corrected by CRISPR/Cas9 technology and the two lines were then used to generate three-dimensional brain organoids in vitro (Yin et al., 2021). 

In addition, several transgenic mice have been created, including NSE-hPS2(N141I) (Hwang et al., 2002), PS2(N141I) (Richards et al., 2003), and PS2(N141I) (Fung et al., 2020). A heterozygous knockin mouse carrying the N141I mutation has also been reported (Nam et al., 2022).

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References

Research Models Citations

1. NSE-hPS2(N141I)
2. PS2(N141I)
3. APP NL-G-F Knock-in

News Citations

1. Lodged in Late Endosomes, Presenilin 2 Churns Out Intraneuronal Aβ 10 Jun 2016
2. Sans Presenilin-2, Lysosomes Struggle. Synapses, Memory Circuits Erode 20 Dec 2024

Paper Citations

1. Murti H, Pieknell K, Bachtiar I, Sulistio YA, Lee SH. Generation of human induced pluripotent stem cell line from Alzheimer's disease patient with PSEN2 N141I mutation using integration-free non-viral method. Stem Cell Res. 2020 Jun 29;47:101892. PubMed.
2. Raska J, Hribkova H, Klimova H, Fedorova V, Barak M, Barta T, Pospisilova V, Vochyanova S, Vanova T, Bohaciakova D. Generation of six human iPSC lines from patients with a familial Alzheimer's disease (n = 3) and sex- and age-matched healthy controls (n = 3). Stem Cell Res. 2021 May;53:102379. Epub 2021 Apr 30 PubMed.
3. Marei HE, Althani A, Afifi N, Hasan A, Caceci T, Pozzoli G, Cenciarelli C. Generation of gene edited hiPSC from familial Alzheimer's disease patient carrying N141I missense mutation in presenilin 2. Stem Cell Res. 2021 Oct;56:102552. Epub 2021 Oct 7 PubMed.
4. Yin J, VanDongen AM. Enhanced Neuronal Activity and Asynchronous Calcium Transients Revealed in a 3D Organoid Model of Alzheimer's Disease. ACS Biomater Sci Eng. 2021 Jan 11;7(1):254-264. Epub 2020 Dec 21 PubMed.
5. Hwang DY, Chae KR, Kang TS, Hwang JH, Lim CH, Kang HK, Goo JS, Lee MR, Lim HJ, Min SH, Cho JY, Hong JT, Song CW, Paik SG, Cho JS, Kim YK. Alterations in behavior, amyloid beta-42, caspase-3, and Cox-2 in mutant PS2 transgenic mouse model of Alzheimer's disease. FASEB J. 2002 Jun;16(8):805-13. PubMed.
6. Richards JG, Higgins GA, Ouagazzal AM, Ozmen L, Kew JN, Bohrmann B, Malherbe P, Brockhaus M, Loetscher H, Czech C, Huber G, Bluethmann H, Jacobsen H, Kemp JA. PS2APP transgenic mice, coexpressing hPS2mut and hAPPswe, show age-related cognitive deficits associated with discrete brain amyloid deposition and inflammation. J Neurosci. 2003 Oct 1;23(26):8989-9003. PubMed.
7. Fung S, Smith CL, Prater KE, Case A, Green K, Osnis L, Winston C, Kinoshita Y, Sopher B, Morrison RS, Garden GA, Jayadev S. Early-Onset Familial Alzheimer Disease Variant PSEN2 N141I Heterozygosity is Associated with Altered Microglia Phenotype. J Alzheimers Dis. 2020;77(2):675-688. PubMed.
8. Nam H, Lee Y, Kim B, Lee JW, Hwang S, An HK, Chung KM, Park Y, Hong J, Kim K, Kim EK, Choe HK, Yu SW. Presenilin 2 N141I mutation induces hyperactive immune response through the epigenetic repression of REV-ERBα. Nat Commun. 2022 Apr 13;13(1):1972. PubMed.
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11. Bird TD, Lampe TH, Nemens EJ, Miner GW, Sumi SM, Schellenberg GD. Familial Alzheimer's disease in American descendants of the Volga Germans: probable genetic founder effect. Ann Neurol. 1988 Jan;23(1):25-31. PubMed.
12. Jayadev S, Leverenz JB, Steinbart E, Stahl J, Klunk W, Yu CE, Bird TD. Alzheimer's disease phenotypes and genotypes associated with mutations in presenilin 2. Brain. 2010 Apr;133(Pt 4):1143-54. PubMed.
13. Blauwendraat C, Wilke C, Jansen IE, Schulte C, Simón-Sánchez J, Metzger FG, Bender B, Gasser T, Maetzler W, Rizzu P, Heutink P, Synofzik M. Pilot whole-exome sequencing of a German early-onset Alzheimer's disease cohort reveals a substantial frequency of PSEN2 variants. Neurobiol Aging. 2016 Jan;37:208.e11-7. Epub 2015 Sep 30 PubMed.
14. Llibre-Guerra JJ, Li Y, Allegri RF, Mendez PC, Surace EI, Llibre-Rodriguez JJ, Sosa AL, Aláez-Verson C, Longoria EM, Tellez A, Carrillo-Sánchez K, Flores-Lagunes LL, Sánchez V, Takada LT, Nitrini R, Ferreira-Frota NA, Benevides-Lima J, Lopera F, Ramírez L, Jiménez-Velázquez I, Schenk C, Acosta D, Behrens MI, Doering M, Ziegemeier E, Morris JC, McDade E, Bateman RJ. Dominantly inherited Alzheimer's disease in Latin America: Genetic heterogeneity and clinical phenotypes. Alzheimers Dement. 2021 Apr;17(4):653-664. Epub 2020 Nov 23 PubMed.
15. Yu CE, Marchani E, Nikisch G, Müller U, Nolte D, Hertel A, Wijsman EM, Bird TD. The N141I mutation in PSEN2: implications for the quintessential case of Alzheimer disease. Arch Neurol. 2010 May;67(5):631-3. PubMed.
16. Müller U, Winter P, Graeber MB. Alois Alzheimer's case, Auguste D., did not carry the N141I mutation in PSEN2 characteristic of Alzheimer disease in Volga Germans. Arch Neurol. 2011 Sep;68(9):1210-1, author reply 1211. PubMed.
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19. Mirra SS, Heyman A, McKeel D, Sumi SM, Crain BJ, Brownlee LM, Vogel FS, Hughes JP, van Belle G, Berg L. The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer's disease. Neurology. 1991 Apr;41(4):479-86. PubMed.
20. Leverenz JB, Fishel MA, Peskind ER, Montine TJ, Nochlin D, Steinbart E, Raskind MA, Schellenberg GD, Bird TD, Tsuang D. Lewy body pathology in familial Alzheimer disease: evidence for disease- and mutation-specific pathologic phenotype. Arch Neurol. 2006 Mar;63(3):370-6. PubMed.
21. Perdok A, Van Acker ZP, Vrancx C, Sannerud R, Vorsters I, Verrengia A, Callaerts-Végh Z, Creemers E, Gutiérrez Fernández S, D'hauw B, Serneels L, Wierda K, Chávez-Gutiérrez L, Annaert W. Altered expression of Presenilin2 impacts endolysosomal homeostasis and synapse function in Alzheimer's disease-relevant brain circuits. Nat Commun. 2024 Nov 29;15(1):10412. PubMed.
22. Walker ES, Martinez M, Brunkan AL, Goate A. Presenilin 2 familial Alzheimer's disease mutations result in partial loss of function and dramatic changes in Abeta 42/40 ratios. J Neurochem. 2005 Jan;92(2):294-301. PubMed.
23. Filadi R, Greotti E, Turacchio G, Luini A, Pozzan T, Pizzo P. Presenilin 2 Modulates Endoplasmic Reticulum-Mitochondria Coupling by Tuning the Antagonistic Effect of Mitofusin 2. Cell Rep. 2016 Jun 7;15(10):2226-38. Epub 2016 May 26 PubMed.
24. Rossini M, García-Casas P, Filadi R, Pizzo P. Loosening ER-Mitochondria Coupling by the Expression of the Presenilin 2 Loop Domain. Cells. 2021 Aug 3;10(8) PubMed.
25. Course MM, Gudsnuk K, Keene CD, Bird TD, Jayadev S, Valdmanis PN. Aberrant splicing of PSEN2, but not PSEN1, in individuals with sporadic Alzheimer's disease. Brain. 2023 Feb 13;146(2):507-518. PubMed.

Other Citations

1. Swedish mutation

Further Reading