Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73640338 A>G
dbSNP ID: rs63750353
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: AAT to GAT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 5


This mutation was identified in a Mexican-American family with a history of early onset dementia spanning at least four generations (Crook et al., 1997). The pedigree contained nine affected individuals and revealed a pattern consistent with autosomal dominant inheritance.

The proband had a history of developmental delay. She was evaluated for symptoms of apathy and depression in her early 30s. Cognitive changes were evident at age 35 and myoclonic jerking began soon after. Ages of onset were known for four additional family members: 34, 34, 36, and 37 years.

Genetic testing was performed in two affected siblings and one unaffected sibling and found to segregate with disease. The N135D mutation in PSEN1 corresponds to the Volga German mutation in PSEN2 (N141I), a highly pathogenic mutation that is the most common PSEN2 mutation worldwide.

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


Biopsy of the proband’s frontal lobe showed mild loss of neurons and secondary gliosis with multiple neuritic plaques and abundant neurofibrillary tangles. It was noted that nearly every neuron contained a tangle. Microglia were increased diffusely and particularly in association with neuritic plaques (Crook et al., 1997).

Biological Effect

When expressed in CHO cells stably transfected with human APP751, the N135D mutation increases intracellular Aβ42 levels and decreases intracellular Aβ40 levels. Similar effects on secreted Aβ40 and Aβ42 were measured in conditioned media (Qi et al., 2003). However, an in vitro assay using purified proteins to test the mutant's ability to cleave the APP-C99 substrate suggests it generates less of both peptides than wild-type PSEN1, but Aβ40 production is more dramatically affected, resulting in an apporoximately 10-fold increase in the Aβ42/Aβ40 ratio (Sun et al., 2017).

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).

Last Updated: 02 Aug 2021


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Paper Citations

  1. . Early-onset Alzheimer's disease with a presenilin-1 mutation at the site corresponding to the Volga German presenilin-2 mutation. Ann Neurol. 1997 Jul;42(1):124-8. PubMed.
  2. . 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.
  3. . 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.
  4. . 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.

Other Citations

  1. N141I

External Citations

  1. gnomAD v2.1.1

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Early-onset Alzheimer's disease with a presenilin-1 mutation at the site corresponding to the Volga German presenilin-2 mutation. Ann Neurol. 1997 Jul;42(1):124-8. PubMed.

Other mutations at this position


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