Mutations

PSEN1 L166P

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease, Spastic Paraparesis
Genomic Mutation Name (MET1): g.38794T>C
Genomic Mutation Name (NT1): g.55399T>C
dbSNP ID: rs63750265
Coding/Non-Coding: Coding
Genomic Region: Exon 6
Mutation Type: Point, Missense
Codon Change: CTT to CCT
Research Models: 1

Findings

This appears to be a relatively rare mutation associated with a very early age of symptom onset. It has been identified in a single family. The female proband developed secondary generalized seizures at age 15, major depression at age 19, and memory impairment by age 24. Ataxia and spastic paraparesis were recorded by age 27, and moderate-stage dementia by 28. Dementia, ataxia, and spasticity progressed until death at age 35. Family history details were not reported (Moehlmann et al., 2002).

Neuropathology

Postmortem examination of the proband’s brain revealed numerous Aβ-positive neuritic and cotton-wool plaques throughout the cerebral cortex. Aβ-positive amyloid cores were abundant in the cerebellar cortex (Moehlmann et al., 2002).

Biological Effect

In vitro, when expressed in HEK293 cells stably expressing APP with the Swedish mutation, mutant PSEN1 caused increased Aβ42 generation and a five- to sixfold increase of the Aβ42/Aβ total ratio. Total levels of Aβ were similar to cells expressing wild-type PSEN1. The mutation also reduced the generation of the APP intracellular domain (AICD) and the Notch intracellular domain (NICD) and impaired Notch signaling (Moehlmann et al., 2002).

Research Models

This mutation has been introduced into mouse models including the double transgenic model, APPPS1, which also expresses APP with the Swedish mutation.

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References

Research Models Citations

  1. APPPS1

Paper Citations

  1. . Presenilin-1 mutations of leucine 166 equally affect the generation of the Notch and APP intracellular domains independent of their effect on Abeta 42 production. Proc Natl Acad Sci U S A. 2002 Jun 11;99(12):8025-30. PubMed.

Further Reading

Papers

  1. . Genetic mutations associated with presenile dementia. Neurobiology of Aging 23 (1S): S322, 2002
  2. . Convergence of pathology in dementia with Lewy bodies and Alzheimer's disease: a role for the novel interaction of alpha-synuclein and presenilin 1 in disease. Brain. 2014 Jul;137(Pt 7):1958-70. Epub 2014 May 24 PubMed.

Learn More

Alzheimer Disease & Frontotemporal Dementia Mutation Database

Primary Papers

  1. . Presenilin-1 mutations of leucine 166 equally affect the generation of the Notch and APP intracellular domains independent of their effect on Abeta 42 production. Proc Natl Acad Sci U S A. 2002 Jun 11;99(12):8025-30. PubMed.

Other mutations at this position

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