Mutations

PSEN2 M174V

Overview

Pathogenicity: Alzheimer's Disease : Not Pathogenic
Clinical Phenotype: Alzheimer's Disease, Frontotemporal Dementia
Coding/Non-Coding: Coding
Genomic Region: Exon 6
Mutation Type: Point, Missense
Codon Change: ATG to GTG

Findings

This PSEN2 variant has been reported in at least four individuals with Alzheimer's disease or frontotemporal dementia, as well as some healthy family members. 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, it may be a risk modifier.

This variant was first reported in 2008, but details were not available (Clarimón et al., 2008; Andreoli et al., 2008).

The M174V variant was subsequently reported in a woman who developed Alzheimer’s disease at age 54. Due to a lack of family history and the fact that this residue is not conserved between presenilin-1 and presenilin-2, M174V was described by the authors as possibly pathogenic (Guerreiro et al., 2010).

A later study found this variant in a family with a history of late-onset AD, but it did not segregate with disease. Specifically, M174V was detected in one affected individual and three healthy family members. In addition, some affected members of the family were not carriers, arguing against pathogenicity (Cruchaga et al., 2012).

Another study reported the M174V mutation in two unrelated Turkish individuals, both exhibiting symptoms consistent with frontotemporal dementia. One patient developed symptoms at age 52, starting with progressive non-fluent aphasia, followed by postural instability, gait disturbance, and dystonia in the right leg. There was a history of neurological disease in the family. The proband's father had Parkinson’s disease and his maternal grandfather died at age 38 from an unspecified neurological disease. His parents were first cousins. The proband's sister was also a mutation carrier. She was healthy at the age of 36.

The second Turkish patient developed changes in mood and personality, notably increased aggression, at age 60. Progressive deficits in speech and attention followed. He was described as having a “frontal syndrome” characterized by a deficit in executive function. His mother had clinically significant memory problems and died at age 64 from a stroke. Segregation with disease could not be determined (Lohmann et al., 2012).

Neuropathology

Unknown. Imaging in one affected carrier showed bilateral atrophy in the parietal lobe and hypoperfusion in temporoparietal regions (Guerreiro et al., 2010). Imaging in the two Turkish individuals with FTD showed cortical and anterior temporal lobe atrophy in one individual and frontal atrophy and hypometabolism in the frontotemporoparietal regions in the other patient (Lohmann et al., 2012).

Biological Effect

Unknown. M174V is located in the third transmembrane domain of PSEN2. The residue is not conserved in presenilin-1. The functional effects of this substitution are not known. It is predicted benign by PolyPhen-2 (Cruchaga et al., 2012; Lohmann et al., 2012).

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References

Paper Citations

  1. . Genetic screening in a large cohort of early-onset Alzheimer's disease patients from Spain: novel mutations in the amyloid precursor protein and presenilines. . Alzheimer's & Dementia 4 Supp 2: T583, 2008
  2. . Gene symbol: PSEN2. Disease: Alzheimer disease. Hum Genet. 2008 Oct;124(3):304. 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.
  5. . Identification of PSEN1 and PSEN2 gene mutations and variants in Turkish dementia patients. Neurobiol Aging. 2012 Aug;33(8):1850.e17-27. PubMed.

Further Reading

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Primary Papers

  1. . Gene symbol: PSEN2. Disease: Alzheimer disease. Hum Genet. 2008 Oct;124(3):304. PubMed.
  2. . Genetic screening in a large cohort of early-onset Alzheimer's disease patients from Spain: novel mutations in the amyloid precursor protein and presenilines. . Alzheimer's & Dementia 4 Supp 2: T583, 2008
  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.