Mutations

PSEN1 L282R

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73664814 T>G
dbSNP ID: rs63750050
Coding/Non-Coding: Coding
Genomic Region: Exon 8
Mutation Type: Point, Missense
Codon Change: CTT to CGT

Findings

This mutation was identified in a Spanish woman affected by early onset Alzheimer’s disease (Aldudo et al., 1998). Clinical onset is considered to have occurred at age 49 and she died at age 54. Details related to her clinical symptoms were not reported. Her mother was affected at age 58, and two of her four siblings were affected, both at age 40. The average age of onset in the family was 43 ± 5 years. The average age of death for affected individuals in the family was 56 ± 3 years. Genetic analysis was only available for the proband, therefore segregation with disease could not be formally demonstrated.

This mutation was also identified in a second Spanish family (Gómez-Tortosa et al., 2010). The proband began to experience memory and concentration difficulties at the age of 35. By the age of 42 she had developed non-fluent aphasia, bilateral myoclonus, generalized seizures and a parkinsonian gait. She had a family history of dementia. Her father was affected by age 42 and died at age 49. Two of the proband’s paternal aunts were affected, at ages 48 and 50, with death at 54 and 58, respectively. Her paternal grandmother was similarly affected and had died at age 58. A brother of the proband was also a mutation carrier. He was clinically presymptomatic at age 37 with signs of hypometabolism in the parietotemporal areas by FDG-PET.

Neuropathology

Autopsy of the proband confirmed neuropathology consistent with the diagnosis of AD (Aldudo et al., 1998).

Biological Effect

Unknown.

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References

Paper Citations

  1. . Identification of a novel mutation (Leu282Arg) of the human presenilin 1 gene in Alzheimer's disease. Neurosci Lett. 1998 Jan 16;240(3):174-6. PubMed.
  2. . Clinical-genetic correlations in familial Alzheimer's disease caused by presenilin 1 mutations. J Alzheimers Dis. 2010;19(3):873-84. PubMed.

Further Reading

Papers

  1. . DGGE method for the mutational analysis of the coding and proximal promoter regions of the Alzheimer's disease presenilin-1 gene: two novel mutations. Hum Mutat. 1999;14(5):433-9. PubMed.
  2. . Clinical-genetic correlations in familial Alzheimer's disease caused by presenilin 1 mutations. J Alzheimers Dis. 2010;19(3):873-84. PubMed.

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Primary Papers

  1. . Identification of a novel mutation (Leu282Arg) of the human presenilin 1 gene in Alzheimer's disease. Neurosci Lett. 1998 Jan 16;240(3):174-6. PubMed.

Other mutations at this position

Alzpedia