Mutations

PSEN1 L235V

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Genomic Mutation Name (MET1): g.44722C>G
Genomic Mutation Name (NT1): g.61328C>G
dbSNP ID: rs63751130
Coding/Non-Coding: Coding
Genomic Region: Exon 7
Mutation Type: Point, Missense
Codon Change: CTG to GTG

Findings

This mutation has been reported in two families from the UK and Mexico. The UK kindred, “Family 267,” included six affected individuals over three generations. The mean age at onset was reported as 47 years with a range of 44-50 years. The diagnosis of Alzheimer's disease was confirmed postmortem in at least one case. The mutation appeared to segregate with disease; it was present in two affected family members. It was absent in 100 unrelated control individuals (Janssen et al., 2003).

The L235V mutation was also reported in a Mexican family with familial dementia starting around age 48. Further clinical details were not described although eleven asymptomatic female family members participated in a depression screen. Mutation carriers had a higher incidence of depression than non-mutation carriers, even when they were naïve to their mutation status, supporting the hypothesis that depression is an early clinical feature related to AD pathology (Ringman et al., 2004).

Neuropathology

Neuropathology consistent with a diagnosis of AD in at least one case (Janssen et al., 2003).

Biological Effect

The association of L235V with depression led researchers to study of the effect of this mutation on monoamine-oxidase-A (MAO-A), an enzyme that degrades serotonin and noradrenaline. Expression of mutant PSEN1 in a murine hippocampal cell line resulted in higher MAO-A activity compared with cells expressing wild-type PSEN1, suggesting that L235V may predispose to depression by affecting neurotransmitter metabolism. In addition, co-immunoprecipitation experiments suggested a possible direct interaction of PSEN1 with MAO-A (Pennington et al., 2011).

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References

Paper Citations

  1. . Early onset familial Alzheimer's disease: Mutation frequency in 31 families. Neurology. 2003 Jan 28;60(2):235-9. PubMed.
  2. . Female preclinical presenilin-1 mutation carriers unaware of their genetic status have higher levels of depression than their non-mutation carrying kin. J Neurol Neurosurg Psychiatry. 2004 Mar;75(3):500-2. PubMed.
  3. . Alzheimer disease-related presenilin-1 variants exert distinct effects on monoamine oxidase-A activity in vitro. J Neural Transm. 2011 Jul;118(7):987-95. PubMed.

Further Reading

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Alzheimer Disease & Frontotemporal Dementia Mutation Database

Primary Papers

  1. . Early onset familial Alzheimer's disease: Mutation frequency in 31 families. Neurology. 2003 Jan 28;60(2):235-9. PubMed.

Other mutations at this position

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