Mutations

PSEN1 N135D

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Genomic Mutation Name (MET1): g.25606A>G
Genomic Mutation Name (NT1): g.42160A>G
dbSNP ID: rs63750353
Coding/Non-Coding: Coding
Genomic Region: Exon 5
Mutation Type: Point, Missense
Codon Change: AAT to GAT

Findings

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 thirties. 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, 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.

Neuropathology

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).

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References

Mutations Citations

  1. PSEN2 N141I

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.

Further Reading

Learn More

Alzheimer Disease & Frontotemporal Dementia Mutation Database

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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