Mutations

PSEN1 Y115C

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73640279 A>G
dbSNP ID: rs63750450
Coding/Non-Coding: Coding
Genomic Region: Exon 5
Mutation Type: Point, Missense
Codon Change: TAT to TGT

Findings

This mutation has been identified in several families over the past two decades.

It was first described in a Dutch family known as Family 1066, whose published pedigree included 10 affected family members over four generations. The clinical diagnosis of Alzheimer’s disease was pathologically confirmed in at least three members of the family. The mean age at onset was 42 years (range: 39 to 49 years). Disease in this family previously had been linked to chromosome 14 (van Duijn et al., 1994). The mutation segregated with disease in this family and was transmitted in an autosomal-dominant manner (Cruts et al., 1998).

The mutation was subsequently detected in one individual during a genetic screen of patients with AD; no further clinical details were reported (Rogaeva et al., 2001).

Another family, known as Family 372, was reported with five affected family members over three generations. The mean age of onset in this family was 48 years (range: 36 to 54 years). No postmortem confirmation of the diagnosis was available at the time of the report (Janssen et al., 2003).

This mutation was also detected in an individual with early onset Alzheimer’s disease, which was confirmed by autopsy. The proband experienced symptom onset at age 43 and died at age 52. The proband’s mother also had early onset dementia (onset at age 33; death at age 42) (unpublished findings, personal communication, T.D. Bird; 2014).

This mutation was reported in an additional kindred. Consistent with the previously reported families, the proband experienced symptom onset in her 40s. She died in her 50s with pathologically confirmed AD. She had a family history of dementia; her mother had experienced a similar disease course. The mutation was also detected in the proband’s daughter, who was asymptomatic at the time (Doran et al., 2006, meeting abstract).

The Y115C mutation was also found in a large French study reporting on 56 families affected by putatively familial early onset Alzheimer disease (Wallon et al., 2012). The Y115C mutation was detected in one proband (family EXT 238). DNA from two affected family members was not available, so segregation with disease could not be determined. Age of onset in this family was reported as 39 to 40 years of age, with a duration of three years.

Neuropathology

Postmortem examination revealed pathology consistent with AD in Family 1066 (van Duijn et al., 1994).

Biological Effect

HEK-293 cells transfected with mutant PSEN1 secreted significantly more Aβ42 (approximately 5.4-fold) than cells expressing wild-type PSEN1. The Aβ42:Aβ40 ratio was also increased (De Jonghe et al., 1999).

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References

Paper Citations

  1. . A population-based study of familial Alzheimer disease: linkage to chromosomes 14, 19, and 21. Am J Hum Genet. 1994 Oct;55(4):714-27. PubMed.
  2. . Estimation of the genetic contribution of presenilin-1 and -2 mutations in a population-based study of presenile Alzheimer disease. Hum Mol Genet. 1998 Jan;7(1):43-51. PubMed.
  3. . Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.
  4. . Early onset familial Alzheimer's disease: Mutation frequency in 31 families. Neurology. 2003 Jan 28;60(2):235-9. PubMed.
  5. Abstracts of the Sixteenth Meeting of the European Neurological Society. May 27-31, 2006. Lausanne, Switzerland. J Neurol. 2006 May;253 Suppl 2:II3-159. 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. . Aberrant splicing in the presenilin-1 intron 4 mutation causes presenile Alzheimer's disease by increased Abeta42 secretion. Hum Mol Genet. 1999 Aug;8(8):1529-40. PubMed.

Further Reading

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Primary Papers

  1. . Estimation of the genetic contribution of presenilin-1 and -2 mutations in a population-based study of presenile Alzheimer disease. Hum Mol Genet. 1998 Jan;7(1):43-51. PubMed.

Other mutations at this position

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