Mutations

PSEN2 R62H

Overview

Pathogenicity: Alzheimer's Disease : Not Pathogenic, Frontotemporal Dementia : Not Pathogenic
Clinical Phenotype: Alzheimer's Disease, Frontotemporal Dementia, Parkinson's Disease Dementia
Genome Build: 105
Position: Chr1:227071449 G>A
dbSNP ID: rs58973334
Coding/Non-Coding: Coding
Genomic Region: Exon 4
Mutation Type: Point, Missense
Codon Change: CGC to CAC

Findings

The R62H variant has been found in people with a variety of neurodegenerative diseases (e.g., Alzheimer's disease, frontotemporal dementia, and Parkinson's disease), as well as in healthy controls. It does not segregate with disease in the families for which data are available, and is therefore not thought to be pathogenic. Although R62H does not appear to cause familial disease, it may be a disease modifier. After correcting for APOE genotype, AD patients carrying the R62H variant were found to have an earlier age of onset than non-carriers (71 versus 75 years) (Cruchaga et al., 2012).

This variant was first reported in a patient with apparently sporadic Alzheimer's disease who developed symptoms at age 62 (Cruts et al., 1998). It was later found in a patient with late-onset Alzheimer's, but it did not segregate with disease within the family (Sleegers et al., 2004).

A large number of control individuals were later found to carry the R62H variant, suggesting it may be a benign polymorphism. Specifically, the R62H variant was found in 20 African individuals, leading the authors to speculate that it may be a relatively common polymorphism in some African populations (Guerreiro et al., 2010).

This variant was also found in a patient diagnosed with frontotemporal dementia. The patient was 31 years old when she began to experience behavioral disturbances and personality changes. The variant did not segregate with disease; it was found in the patient's cognitively healthy mother but was absent in an affected sibling (Gallo et al., 2010).

The variant was also found in a Turkish man with a family history of AD. The proband developed symptom onset at age 63 and developed symptoms of parkinsonism. The reported pedigree shows that his mother and maternal grandmother were also affected by dementia with apparent autosomal-dominant transmission. Segregation with disease could not be determined due to lack of DNA from family members (Lohmann et al., 2012).

This variant was also found in an individual with idiopathic Parkinson's disease with dementia (Schulte et al., 2015). The patient first developed symptoms of bradykinesia at age 81 and had a three-year disease duration. Other symptoms included rigidity and postural instability. The PD phenotype in this individual is considered unlikely to be attributable to the presence of this variant.

Most recently, this variant was found in one out of 72 individuals with AD. There was no family history of AD, and the clinical details related to this case were not reported (Frigerio et al., 2015).

Neuropathology

Unknown.

Biological Effect

This arginine, located in the N-terminal of PSEN2, is conserved between PSEN1 and PSEN2 (it is R60 in PSEN1). When transfected into fibroblasts lacking endogenous PSEN1 or PSEN2, the R62H variant did not affect steady-state levels of the proteolytic products PSEN2-CTF and PSEN2-NTF compared with wild-type PSEN2. When co-transfected with APP carrying the Swedish mutation, the R62H mutation did not affect Aβ42 levels or the Aβ42/Aβ40 ratio (Walker et al., 2005). Similar results were seen in HEK293 cells (To et al., 2006).

In silico the R62H variant is predicted benign by PolyPhen2. 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

Mutations Citations

  1. APP KM670/671NL (Swedish)

Paper Citations

  1. . 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.
  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. . 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.
  4. . 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.
  5. . Novel MAPT Val75Ala mutation and PSEN2 Arg62Hys in two siblings with frontotemporal dementia. Neurol Sci. 2010 Feb;31(1):65-70. Epub 2009 Sep 19 PubMed.
  6. . Identification of PSEN1 and PSEN2 gene mutations and variants in Turkish dementia patients. Neurobiol Aging. 2012 Aug;33(8):1850.e17-27. PubMed.
  7. . Rare variants in β-Amyloid precursor protein (APP) and Parkinson's disease. Eur J Hum Genet. 2015 Jan 21; PubMed.
  8. . On the identification of low allele frequency mosaic mutations in the brains of Alzheimer's disease patients. Alzheimers Dement. 2015 Apr 29; PubMed.
  9. . Presenilin 2 familial Alzheimer's disease mutations result in partial loss of function and dramatic changes in Abeta 42/40 ratios. J Neurochem. 2005 Jan;92(2):294-301. PubMed.
  10. . Functional characterization of novel presenilin-2 variants identified in human breast cancers. Oncogene. 2006 Jun 15;25(25):3557-64. PubMed.

Further Reading

Papers

  1. . Plasma amyloid beta protein is elevated in late-onset Alzheimer disease families. Neurology. 2008 Feb 19;70(8):596-606. Epub 2007 Oct 3 PubMed.

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.
  2. . Novel MAPT Val75Ala mutation and PSEN2 Arg62Hys in two siblings with frontotemporal dementia. Neurol Sci. 2010 Feb;31(1):65-70. Epub 2009 Sep 19 PubMed.

Other mutations at this position

Alzpedia