Mutations

PSEN1 E184G

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73659354 A>G
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GAA to GGA
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This 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 E184G mutation was initially identified in two families, ALZ 013 and EXT 134. The ALZ 013 family had two confirmed mutation carriers and eight affected family members. The age of onset in this family ranged from 43 to 52 years, and disease duration ranged from five to 14 years. The mutation appears to segregate with disease in this family. The EXT 134 family had two mutation carriers and three affected family members. In this family symptoms started at age 51 or 52, with a duration of seven to eight years. Segregation with disease could not be definitively determined. An unspecified number of mutation carriers developed symptoms consistent with a frontal variant of AD and were affected by early myoclonic epilepsy. In a subsequent study, seizures were reported in two of three French mutation carriers with average age at onset of 44.5 years (Zarea et al. 2016). The average time between AD onset and first seizure was eight years.

The mutation was also found in in a 41-year-old Thai woman with memory loss and a family history of dementia (Giau et al., 2019, Senanarong et al., 2020). The father and grandfather of the patient were diagnosed with dementia. In the patient, no additional mutations were found in 50 genes related to neurodegenerative disease. The mutation was absent from several variant databases, including KRGDB, ExAC, and 1000Genomes.

Neuropathology

Although neuropathological data are unavailable, MRI in one patient revealed global cortical atrophy (Senanarong et al., 2020).

Biological Effect

An in vitro assay using purified proteins to test this mutant's ability to cleave the APP-C99 substrate revealed it generates less Aβ42, and particularly less Aβ40, than wild-type PSEN1, resulting in an approximately five-fold elevation of the Aβ42/Aβ40 ratio (Sun et al., 2017). Moreover, the mutation may disturb splicing near exon 7 (Giau et al., 2019). Three pathogenicity-predicting algorithms--PolyPhen2, Sift, and Provean--classified the mutation as damaging. In addition, 3-D modeling predicted structural changes, possibly including increased flexibility of PSEN1's third transmembrane helix, as well as disruption of inter- and/or intra-helical interactions (Senanarong et al., 2020).

Last Updated: 04 Mar 2020

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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. . Seizures in dominantly inherited Alzheimer disease. Neurology. 2016 Aug 30;87(9):912-9. Epub 2016 Jul 27 PubMed.
  3. . Analysis of 50 Neurodegenerative Genes in Clinically Diagnosed Early-Onset Alzheimer's Disease. Int J Mol Sci. 2019 Mar 26;20(6) PubMed.
  4. . Pathogenic PSEN1 Glu184Gly Mutation in a Family from Thailand with Probable Autosomal Dominant Early Onset Alzheimer's Disease. Diagnostics (Basel). 2020 Mar 1;10(3) PubMed.
  5. . Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase. Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E476-E485. Epub 2016 Dec 5 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.

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