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 has been reported in at least four individuals with late-onset Alzheimer's disease. Currently, there is no evidence that it segregates with disease, and in fact, it has been shown not to segregate with disease in one family. Although not causative, R71W may be a disease modifier.

The R71W variant was first identified in a Caucasian patient with late-onset Alzheimer's disease. In the same study it was also found in one of 283 healthy controls (Sleegers et al., 2004).

The R71W variant was subsequently reported in two more patients with late-onset AD (Brouwers et al., 2008; Guerreiro et al., 2010).

The R71W variant was also found in a woman from Macedonia who developed apparently sporadic AD at the age of 64. Her symptoms were described as fairly typical of AD, with the addition of a hand tremor. She had no known family history of dementia, but her mother had died at age 20 from tuberculosis, and information relating to the maternal line was unknown (Lohmann et al., 2012).

Another recent study detected the R71W variant 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. The authors noted that the R71W mutation was associated with an earlier age at onset, 70.2 years versus 76.7 years in non-carriers, suggesting that R71W may be a disease modifier (Cruchaga et al., 2012).

Neuropathology

Unknown. 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. In silico, this variant has been predicted probably damaging by PolyPhen-2 (Cruchaga et al., 2012). It has been classified as not pathogenic according to the algorithm proposed by Guerreiro et al., 2010 (Lohmann 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. . Identification of PSEN1 and PSEN2 gene mutations and variants in Turkish dementia patients. Neurobiol Aging. 2012 Aug;33(8):1850.e17-27. PubMed.
  5. . 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.