Mutations

PSEN1 L262V

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease, Frontotemporal Dementia
Reference Assembly: GRCh37 (105)
Position: Chr14:73664753 T>G
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: TTG to GTG
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

The L262V mutation was found in a large French study reporting 56 new families with autosomal-dominant, early onset Alzheimer's disease. All probands met NINCDS-ADRDA criteria for probable AD and had a family history of disease (Wallon et al., 2012).

The mutation was detected in one family with three confirmed carriers and eight affected family members. Age of onset ranged from 54 to 63 years old, with a disease duration of approximately eight years. The mutation appears to segregate with disease in this family.

Another study reported the L262V mutation in two Turkish siblings with a family history of dementia (Lohmann et al., 2012). Both siblings developed symptoms around age 50; however, the presenting symptoms were different, leading to diagnoses of AD and frontotemporal dementia, respectively. One sibling presented with depression, inappropriate behavior, and memory problems. Frontal symptoms then developed, including disinhibited speech and perseveration, along with temporospatial disorientation. Prominent symptoms in the other sibling included disorientation, aphasia, and memory deficits.

The mother of these two patients, as well as their maternal aunt, reportedly suffered from dementia. Both died at approximately 70 years of age after a rapid decline. A cousin was also affected by memory problems, bringing the number of affected individuals up to five in two generations, as shown in the reported pedigree, which indicates at least two consanguineous marriages.

Neuropathology

Unknown.

Biological Effect

Unknown. In silico this mutation is predicted probably damaging by PolyPhen-2. The L262V mutation has been classified as definitely pathogenic according to the algorithm proposed by Guerreiro et al., 2010.

 

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References

Paper Citations

  1. . The French series of autosomal dominant early onset Alzheimer's disease cases: mutation spectrum and cerebrospinal fluid biomarkers. J Alzheimers Dis. 2012 Jan 1;30(4):847-56. PubMed.
  2. . Identification of PSEN1 and PSEN2 gene mutations and variants in Turkish dementia patients. Neurobiol Aging. 2012 Aug;33(8):1850.e17-27. 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.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . The French series of autosomal dominant early onset Alzheimer's disease cases: mutation spectrum and cerebrospinal fluid biomarkers. J Alzheimers Dis. 2012 Jan 1;30(4):847-56. PubMed.
  2. . Identification of PSEN1 and PSEN2 gene mutations and variants in Turkish dementia patients. Neurobiol Aging. 2012 Aug;33(8):1850.e17-27. PubMed.

Other mutations at this position

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