Mutations

PSEN2 R71W

Overview

Pathogenicity: Alzheimer's Disease : Not Pathogenic
Clinical Phenotype: Alzheimer's Disease, None
Genomic Mutation Name (MET1): g.1855C>T
Genomic Mutation Name (NT1): g.18203C>T
dbSNP ID:
Coding/Non-Coding: Coding
Genomic Region: Exon 4
Mutation Type: Point, Missense
Codon Change: CGG to TGG

Findings

This PSEN2 variant was first identified in a Caucasian patient with probable late-onset Alzheimer's disease; however, in the same study it was also found in one of 283 healthy controls (Sleegers et al., 2004). It was subsequently reported in two more patients with late-onset AD (Brouwers et al., 2008; Guerreiro et al., 2010). A later study found R71W in six families with a history of familial late-onset AD, but the mutation did not segregate with disease. Specifically, it was found in six affected individuals and three healthy individuals. In addition, it was absent in eight affected family members, arguing against pathogenicity. However, the authors noted that the R71W mutation was associated with a significantly earlier age at onset (70.2 versus 76.7 years in noncarriers), suggesting that while not causative, R71W may be a disease modifier (Cruchaga et al., 2012).

Neuropathology

Neuroimaging data were available for one mutation carrier with late-onset AD. The patient was described as having leukoencephalopathy with periventricular white matter lacunar infarctions (Guerreiro et al., 2010).

Biological Effect

Unknown, but predicted "probably damaging" by PolyPhen-2 (Cruchaga et al., 2012).

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References

Paper Citations

  1. . Familial clustering and genetic risk for dementia in a genetically isolated Dutch population. Brain. 2004 Jul;127(Pt 7):1641-9. Epub 2004 May 6 PubMed.
  2. . Molecular genetics of Alzheimer's disease: an update. Ann Med. 2008;40(8):562-83. PubMed.
  3. . 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.
  4. . Rare variants in APP, PSEN1 and PSEN2 increase risk for AD in late-onset Alzheimer's disease families. PLoS One. 2012;7(2):e31039. PubMed.

Further Reading

Learn More

Alzheimer Disease & Frontotemporal Dementia Mutation Database

Primary Papers

  1. . Familial clustering and genetic risk for dementia in a genetically isolated Dutch population. Brain. 2004 Jul;127(Pt 7):1641-9. Epub 2004 May 6 PubMed.