Mutations

PSEN1 A260V

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73664748 C>T
dbSNP ID: rs63751420
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GCT to GTT
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

This mutation was originally reported in two families of Japanese origin (Rogaev et al., 1995; Ikeda et al., 1996; Poorkaj et al., 1998). In the more well-characterized family, at least 10 members, across three generations, suffered from AD symptoms, usually beginning with personality changes and memory loss at a mean age of 40 years (Ikeda et al., 1996). The mutation was present in all four affected members who were tested, and absent from 140 Japanese and 200 white controls.
The mutation has also been found in several non-Asian families. It was identified in an AD patient in the U.K. with six family members across two generations presenting with AD symptoms beginning at ages 40–42 (Janssen et al., 2003). Moreover, it was found in a woman from the Iberian peninsula who developed AD symptoms at age 30 and had a family history of dementia emerging before age 40 (Guerreiro et al., 2010). The mutation was also found in a member of a French family with six affected individuals with age of onset ranging between 34 and 38 years (Wallon et al., 2012). 

Neuropathology
In three cases from the Japanese pedigree, neuropathology was consistent with AD, including widespread senile plaques, neurofibrillary tangles, and neuronal loss. In addition, abundant perivascular amyloid deposits were found in the subpial regions of Virchow-Robin spaces and Pick-like intraneuronal inclusions were observed in the dentate gyrus (Ikeda et al., 1996).

Biological Effect
In the conditioned media of COS-1 cells transfected with cDNAs encoding APP695 and the A260V mutant, the Aβ42/Aβ ratio was increased relative to controls (Murayama et al., 1999). Consistent with this finding, an in vitro assay using the APP-C99 substrate revealed an approximately 18-fold increase in the Aβ42/Aβ40 ratio (Sun et al., 2017). The mutant produced less of both Aβ42 and Aβ40, but the drop in Aβ40 production was greater. Decreased Aβ production was also reported in PC12D transfected cells (Kametani et al., 2004). Moreover, a reduction in Rab8, a GTPase involved in vesicular transport, and disruption of the intracellular distribution of the APP C-terminal fragment was observed in these cells.

Last Updated: 03 Apr 2019

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References

Paper Citations

  1. . Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene. Nature. 1995 Aug 31;376(6543):775-8. PubMed.
  2. . The clinical phenotype of two missense mutations in the presenilin I gene in Japanese patients. Ann Neurol. 1996 Dec;40(6):912-7. PubMed.
  3. . Missense mutations in the chromosome 14 familial Alzheimer's disease presenilin 1 gene. Hum Mutat. 1998;11(3):216-21. PubMed.
  4. . Early onset familial Alzheimer's disease: Mutation frequency in 31 families. Neurology. 2003 Jan 28;60(2):235-9. PubMed.
  5. . Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP. Neurobiol Aging. 2010 May;31(5):725-31. Epub 2008 Jul 30 PubMed.
  6. . The French series of autosomal dominant early onset Alzheimer's disease cases: mutation spectrum and cerebrospinal fluid biomarkers. J Alzheimers Dis. 2012 Jan 1;30(4):847-56. PubMed.
  7. . Enhancement of amyloid beta 42 secretion by 28 different presenilin 1 mutations of familial Alzheimer's disease. Neurosci Lett. 1999 Apr 9;265(1):61-3. PubMed.
  8. . 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.
  9. . Mutant presenilin (A260V) affects Rab8 in PC12D cell. Neurochem Int. 2004 Apr;44(5):313-20. PubMed.

Further Reading

Papers

  1. . Human wild presenilin-1 mimics the effect of the mutant presenilin-1 on the processing of Alzheimer's amyloid precursor protein in PC12D cells. J Neurol Sci. 2001 Jul 15;188(1-2):27-31. PubMed.

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Protein Diagram

Primary Papers

  1. . Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene. Nature. 1995 Aug 31;376(6543):775-8. PubMed.
  2. . The clinical phenotype of two missense mutations in the presenilin I gene in Japanese patients. Ann Neurol. 1996 Dec;40(6):912-7. PubMed.

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