Mutations

PSEN1 G384A

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Genome Build: GRCh37 (105)
Position: Chr14:73683855 G>C
dbSNP ID: rs63750646
Coding/Non-Coding: Coding
Genomic Region: Exon 11
Mutation Type: Point, Missense
Codon Change: GGA to GCA

Findings

This mutation was first identified by linkage analysis in a large Belgian family affected by early onset Alzheimer’s disease (Cruts et al., 1995). The family, known as AD/B, included at least 16 affected individuals over five generations. The average age of onset was 35 (34.7 ± 3.0 years). The diagnosis of AD was confirmed in several family members at autopsy. Clinical information related to this family was reported in Martin et al., 1991.

A Japanese family with this mutation has also been identified (Tanahashi et al., 1996). This family, known as FAD-Yg, included four family members affected by early onset AD. Symptom onset ranged from 31 to 37 years old. Two family members had postmortem confirmed AD.

Neuropathology

Neuropathology consistent with AD was observed in members of the AD/B family. In addition to typical AD pathology of cortical plaques and tangles, amyloid plaques were also noted in the cerebellum. Typical AD pathology was observed in at least two members of the FAD-Yg family from Japan (Tanahashi et al., 1996).

Biological Effect

When transfected into HEK293 cells stably expressing Swedish mtAPP695 and BACE1, this mutation impaired the carboxypeptidase-like γ-cleavage, but spared the endoproteolytic ε-cleavage activity of PSEN1. This resulted in reduced secreted Aβ40, increased Aβ42, and an elevated Aβ42/Aβ40 ratio (Li et al., 2016). Additionally, this mutation caused PSEN1 to localize to endolysosomal compartments, similar to the distribution of PSEN2. This resulted in altered substrate specificity and an increased Aβ42/Aβ40 ratio in the intracellular pool of Aβ (Sannerud et al., 2016; see May 2016 news).

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References

News Citations

  1. Lodged in Late Endosomes, Presenilin 2 Churns Out Intraneuronal Aβ

Paper Citations

  1. . Molecular genetic analysis of familial early-onset Alzheimer's disease linked to chromosome 14q24.3. Hum Mol Genet. 1995 Dec;4(12):2363-71. PubMed.
  2. . Early-onset Alzheimer's disease in 2 large Belgian families. Neurology. 1991 Jan;41(1):62-8. PubMed.
  3. . Sequence analysis of presenilin-1 gene mutation in Japanese Alzheimer's disease patients. Neurosci Lett. 1996 Nov 1;218(2):139-41. PubMed.
  4. . Effect of Presenilin Mutations on APP Cleavage; Insights into the Pathogenesis of FAD. Front Aging Neurosci. 2016;8:51. Epub 2016 Mar 11 PubMed.
  5. . Restricted Location of PSEN2/γ-Secretase Determines Substrate Specificity and Generates an Intracellular Aβ Pool. Cell. 2016 Jun 30;166(1):193-208. Epub 2016 Jun 9 PubMed.

Further Reading

Papers

  1. . Familial Alzheimer's disease genes in Japanese. J Neurol Sci. 1998 Sep 18;160(1):76-81. PubMed.

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database
  2. Japanese Familial Alzheimer's Disease Database

Primary Papers

  1. . Molecular genetic analysis of familial early-onset Alzheimer's disease linked to chromosome 14q24.3. Hum Mol Genet. 1995 Dec;4(12):2363-71. PubMed.
  2. . Sequence analysis of presenilin-1 gene mutation in Japanese Alzheimer's disease patients. Neurosci Lett. 1996 Nov 1;218(2):139-41. PubMed.

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