Mutations

PSEN1 G378V

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73683837 G>T
dbSNP ID: rs63750323
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GGA to GTA
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 11

Findings

This mutation was originally identified in a family from the United Kingdom. The family, identified as Family 134, had 13 members affected by Alzheimer’s disease over three generations. The average age of onset was 43 (range: 41-49 years). The mutation was found in three affected family members and was determined to segregate with disease (Janssen et al., 2003).

This mutation was later found in a Hispanic woman from Florida with early onset AD. She had a positive family history but details were not reported. Age of onset is unknown; she died at age 51 (Ravenscroft et al., 2016).

The mutation was also identified in two members of a Canadian family diagnosed with probable and possible corticobasal syndrome (Lam et al., 2017).  The age at onset for these patients was 43 and 45 years, respectively. Initial symptoms included inattention, memory impairment, personality change, and in one case, depressed mood.

Neuropathology

Some affected members of Family 134 had autopsy-confirmed AD (Janssen et al., 2003). MRI scans of the Canadian patients revealed moderate atrophy of the side of the brain contralateral to their affected hemibody in one case, and generalized atrophy in the other (Lam et al., 2017). SPECT showed hypoperfusion of contralateral temporal and parietal regions in one case, and frontal cortex in the other.

Biological Effect

In vitro assays with isolated proteins indicate this mutation dramatically decreases Aβ42 and Aβ40 production (Sun et al., 2017). The levels of Aβ40 were undetectable. The mutation was predicted to be damaging by in silico analyses using SIFT, Polyphen, and Mutation Taster (Lam et al., 2017).

A cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates that G378 forms part of one of two PSEN1 β-strands induced by APP binding. These strands, together with an APP β-strand, form a hybrid, three-stranded β–sheet that appears to be indispensable for cleavage (Zhou et al., 2019; Jan 2019 news).

Last Updated: 09 Aug 2019

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References

News Citations

  1. CryoEM γ-Secretase Structures Nail APP, Notch Binding

Paper Citations

  1. . Early onset familial Alzheimer's disease: Mutation frequency in 31 families. Neurology. 2003 Jan 28;60(2):235-9. PubMed.
  2. . The presenilin 1 p.Gly206Ala mutation is a frequent cause of early-onset Alzheimer's disease in Hispanics in Florida. Am J Neurodegener Dis. 2016;5(1):94-101. Epub 2016 Mar 1 PubMed.
  3. . Characterizing familial corticobasal syndrome due to Alzheimer's disease pathology and PSEN1 mutations. Alzheimers Dement. 2016 Oct 12; PubMed.
  4. . 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.
  5. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.

Further Reading

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Protein Diagram

Primary Papers

  1. . Early onset familial Alzheimer's disease: Mutation frequency in 31 families. Neurology. 2003 Jan 28;60(2):235-9. PubMed.

Other mutations at this position

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