Mutations

PSEN1 G206A

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Genomic Mutation Name (MET1): g.44636G>C
Genomic Mutation Name (NT1): g.61242G>C
dbSNP ID: rs63750082
Coding/Non-Coding: Coding
Genomic Region: Exon 7
Mutation Type: Point, Missense
Codon Change: GGT to GCT

Findings

This mutation was found in five of 414 patients screened for familial Alzheimer’s disease. The five patients represented four putatively unrelated families (two of the patients were siblings). All five mutation carriers were of Hispanic ethnicity (see note in Athan et al., 2001), but additional demographic and clinical details were not reported (Rogaeva et al., 2001).

In a study of 19 Caribbean-Hispanic families affected by early-onset AD, eight probands were found to carry the G206A mutation. The families originated from Puerto Rico and the Dominican Republic, and although the pedigrees were not known to intersect, microsatellite testing revealed a common ancestor. The G206A mutation was found in 23 of the 44 individuals tested from the eight families. The majority of mutation carriers (21 of 23) had AD at the time of genetic testing and the other two carriers met criteria for mild cognitive impairment (Petersen et al., 1999) at age 52 and 57. In addition, five family members had AD but did not carry the mutation; however, their mean age at onset was significantly later (68.9 ± 9.5 years) than observed in mutation carriers (54.5 ± 7.1 years), and three were homozygous for APOE4 (Athan et al., 2001).

The clinical phenotypes associated with the G206A mutation have not been described in detail, but one mutation carrier of Caribbean-Hispanic descent has been described as presenting with cognitive impairment and delusions. He was also noted to have an adverse reaction to a neuroleptic agent, manifesting as extrapyramidal side effects, which resolved after the treatment was discontinued (Cercy et al., 2008).

Neuropathology

Unknown.

Biological Effect

When co-expressed in HEK-293 cells expressing APP with the Swedish mutation, the mutant presenilin-1 produced a 2.2-fold increase in secreted Aβ42 compared with cells expressing wild-type presenilin-1. Secreted Aβ40 levels were comparable between the two cell lines (Athan et al., 2001).

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References

Mutations Citations

  1. APP KM670/671NL (Swedish)

Paper Citations

  1. . A founder mutation in presenilin 1 causing early-onset Alzheimer disease in unrelated Caribbean Hispanic families. JAMA. 2001 Nov 14;286(18):2257-63. PubMed.
  2. . Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.
  3. . Mild cognitive impairment: clinical characterization and outcome. Arch Neurol. 1999 Mar;56(3):303-8. PubMed.
  4. . Prominent neuroleptic sensitivity in a case of early-onset Alzheimer disease due to presenilin-1 G206A mutation. Cogn Behav Neurol. 2008 Sep;21(3):190-5. PubMed.

Further Reading

Learn More

Alzheimer Disease & Frontotemporal Dementia Mutation Database

Primary Papers

  1. . Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.
  2. . A founder mutation in presenilin 1 causing early-onset Alzheimer disease in unrelated Caribbean Hispanic families. JAMA. 2001 Nov 14;286(18):2257-63. PubMed.

Other mutations at this position

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