NM_000447.2(PSEN2):c.422A>T (p.Asn141Ile) AND Alzheimer disease, type 4

Clinical significance:Pathogenic (Last evaluated: Sep 1, 2011)

Review status:(0/4)0 stars out of maximum of 4 stars

no assertion criteria provided

Based on:
2 submissions [Details]
Record status:

Allele description [Variation Report for NM_000447.2(PSEN2):c.422A>T (p.Asn141Ile)]

NM_000447.2(PSEN2):c.422A>T (p.Asn141Ile)

PSEN2:presenilin 2 [Gene - OMIM]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_000447.2(PSEN2):c.422A>T (p.Asn141Ile)
  • NC_000001.11:g.226885603A>T
  • NG_007381.1:g.20032A>T
  • NM_000447.2:c.422A>T
  • NP_000438.2:p.Asn141Ile
  • NC_000001.10:g.227073304A>T
  • NM_000447.1:c.422A>T
Protein change:
N141I; ASN141ILE
OMIM: 600759.0001; dbSNP: 63750215
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_000447.2:c.422A>T - missense variant - [Sequence Ontology: SO:0001583]


Alzheimer disease, type 4 (AD4)
MedGen: C1847200; Orphanet: 1020; OMIM: 606889
Age of onset:
1-9 / 100 000 1020

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000029611OMIMno assertion criteria providedPathogenic
(Sep 1, 2011)
germlineliterature only

PubMed (6)
[See all records that cite these PMIDs]

Levy-Lahad, E., Wasco, W., Poorkaj, P., Romano, D. M., Oshima, J., Pettingell, W. H., Yu, C., Jondro, P. D., Schmidt, S. D., Wang, K., Crowley, A. C., Fu, Y.-H., Guenette, S. Y., Galas, D., Nemens, E., Wijsman, E. M., Bird, T. D., Schellenberg, G. D., Tanzi, R. E. Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science 269: 973-977, 1995.,

SCV000040676GeneReviewsno assertion criteria providedpathologic
(Dec 23, 2010)
not providedcuration

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only
not providednot providednot providednot providednot providednot providednot providednot providedliterature only



Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene.

Rogaev EI, Sherrington R, Rogaeva EA, Levesque G, Ikeda M, Liang Y, Chi H, Lin C, Holman K, Tsuda T, et al.

Nature. 1995 Aug 31;376(6543):775-8.

PubMed [citation]

The presenilin 2 mutation (N141I) linked to familial Alzheimer disease (Volga German families) increases the secretion of amyloid beta protein ending at the 42nd (or 43rd) residue.

Tomita T, Maruyama K, Saido TC, Kume H, Shinozaki K, Tokuhiro S, Capell A, Walter J, Gr├╝nberg J, Haass C, Iwatsubo T, Obata K.

Proc Natl Acad Sci U S A. 1997 Mar 4;94(5):2025-30.

PubMed [citation]
See all PubMed Citations (6)

Details of each submission

From OMIM, SCV000029611.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (6)


In a total of 7 Volga German families with early-onset familial Alzheimer disease (AD4; 606889), Levy-Lahad et al. (1995) found an A-T transversion in the PSEN2 gene, resulting in an asn141-to-ile (N141I) substitution.

In 3 of 4 pedigrees of Volga German ancestry, Rogaev et al. (1995) found heterozygosity for the N141I mutation, suggesting founder effect.

To gain insight into the significance of the presenilins in the pathogenetic mechanisms of early-onset familial Alzheimer disease, Tomita et al. (1997) expressed cDNAs for wildtype PSEN2 and PSEN2 with the Volga German mutation (N141I) in cultured cells and then examined the metabolism of the transfected proteins and their effect on the C-terminal properties of secreted amyloid beta protein (A-beta). PSEN2 was identified as a 50- to 55-kD protein that was cleaved to produce N-terminal fragments of 35 to 40 kD and C-terminal fragments of 19 to 23 kD. The N141I mutation did not cause any significant change in the metabolism of PSEN2. COS-1 cells doubly transfected with the mutant N141I PSEN2 gene and human beta-amyloid precursor protein, as well as mouse neuroblastoma cells stably transfected with N141I mutant PSEN2 alone, secreted 1.5- to 10-fold more beta-amyloid 42 or 43 compared with those expressing the wildtype PSEN2. These results strongly suggested to Tomita et al. (1997) that the N141I mutation linked to FAD alters the metabolism of APP to foster the production of the form of A-beta that most readily deposits in amyloid plaques. Thus, mutant PSEN2 may lead to AD by altering the metabolism of APP.

Marambaud et al. (1998) showed that the expression of wildtype PSEN2 in human HEK293 cells increases the production of the physiologic alpha-secretase-derived product APP-alpha. By contrast, APP-alpha secretion was drastically reduced in cells expressing the N141I mutation of PSEN2.

Wijsman et al. (2005) noted the wide range in age at onset of Alzheimer disease in Volga German families with the N141I mutation in PSEN2. To examine evidence for a genetic basis for the variation in age at onset, the authors performed a Bayesian oligogenic segregation and linkage analysis on 9 Volga German families known to have a least 1 affected PSEN2 mutation carrier. The analysis was designed to estimate the effects of APOE and PSEN2 and the number and effects of additional loci and the environment (family effects) affecting age at onset of AD. The analysis showed that APOE plays a small but significant role in modifying the age at onset in these Volga German families. There was evidence of a dose-dependent relationship between the number of E4 alleles and age at onset. Wijsman et al. (2005) calculated an approximately 83% posterior probability of at least one modifier locus in addition to APOE; the fraction of the variance in age at onset attributable to PSEN2, APOE, other loci, and family effects was approximately 70%, 2%, 6.5%, and 8.5%, respectively.

Yu et al. (2010) demonstrated that a family from Fulda (Hesse), Germany with AD4 caused by the N141I mutation shared the same haplotype as the Volga German families reported earlier. This finding indicated that the mutation must have occurred prior to the emigration of the Volga Germans from the Hesse region of Germany to Russia in the 1760s during the reign of Catherine the Great. In addition, the original patient with AD reported by Alzheimer (1907) also lived in the same Hesse region as the modern family, which raised the possibility that the original patient may have had the N141I mutation. However, Muller et al. (2011) sequenced exon 5 of the PSEN2 gene in DNA extracted from a tissue section prepared from the brain of the original patient with AD ('Auguste D'), and found that she did not carry the N141I mutation, thus disproving the hypothesis of Yu et al. (2010).

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

From GeneReviews, SCV000040676.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1not providednot providednot providednot providedAssert pathogenicitynot providednot providednot providednot provided

Last Updated: Oct 11, 2015