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 presenilin-1 mutation was identified in 2001 in a group of families from Puerto Rico and the Dominican Republic (Athan et al. 2001; Rogaeva et al., 2001). The G206A mutation is now linked to Alzheimer's disease in 70 families, all of Caribbean-Hispanic ancestry, and may be the most common cause of familial AD in this population (Lee et al., 2014). The G206A mutation is associated with a particularly variable age at onset, generally ranging from about 40 to 73 years of age, with some individuals remaining free of clinical symptoms into their 90s.

The G206A mutation was first reported in five of 414 patients screened for familial Alzheimer’s disease (Rogaeva et al., 2001). The five mutation carriers represented four putatively unrelated families (two  were siblings). All five carriers were of Hispanic ethnicity (see note in Athan et al., 2001), but additional demographic and clinical details were not reported.

In a study of 19 Caribbean-Hispanic families affected by early onset AD, eight probands were found to carry the G206A mutation. The families all originated from Puerto Rico and the Dominican Republic, and microsatellite testing revealed a common ancestor. The mutation did not strictly segregate with disease; five family members had AD but were not mutation carriers. However, the mean age at onset was earlier in mutation carriers (54.5 ± 7.1 years) than in non-carriers (68.9 ± 9.5 years), suggesting that disease in the latter group may have been sporadic (three were homozygous for APOE4) (Athan et al., 2001).

The clinical phenotypes associated with the G206A mutation have not been reported in detail, but one mutation carrier of Caribbean-Hispanic descent presented with cognitive impairment and delusions (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. . Disease-related mutations among Caribbean Hispanics with familial dementia. Mol Genet Genomic Med. 2014 Sep;2(5):430-7. Epub 2014 Jun 4 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

View Table