Mutations

PSEN1 R377W

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73683833 A>T
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: AGG to TGG
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 10

Findings

This mutation has been reported in three unrelated European individuals with Alzheimer's disease, two with family histories of dementia. The associated phenotypes are heterogeneous, including  variable age at onset. The mutation is absent from the gnomAD and the Exome Variant Server databases.

The mutation was first reported 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 R377W mutation was detected in one individual in a family with two additional affected individuals. Only the genotype of the proband is known, therefore segregation with disease could not be determined. Age of onset in this family was around 50, with an eight- to nine-year clinical disease course. The mutation was classified as probably pathogenic according to the algorithm proposed by Guerreiro et al., 2010.

This mutation was also detected in an Italian man diagnosed with late-onset AD, who exhibited an atypical presentation including seizures and prominent behavioral symptoms (Borroni et al., 2011). He was 60 years old when he developed epileptic seizures, followed six years later by cognitive impairment, language deficits, apathy, and appetite changes. He did not have a family history of disease; his parents died at age 67 and 92 without cognitive deficits, and two siblings were healthy at age 58 and 65. 

More recently, the mutation was found in a 71-year-old Italian woman with progressive cognitive decline starting at age 67 and a family history of dementia (Scarioni et al., 2020). There is no indication that she is related to the previously described Italian carrier, but the two individuals are from nearby regions in Northern Italy, and thus might share a common ancestor. The woman suffered from episodic memory impairment, disorientation, and apraxia, but also had symptoms of the behavioral variant of AD, including disinhibition, apathy, lack of empathy, obsessiveness, and craving for sweets. Age at onset in four of her family members ranged from 45 to 65, and disease duration from five to 15 years. All affected members developed dementia with mixed memory and behavioral/psychiatric symptoms. No signs of language impairment or epileptic activity were observed in the proband nor reported in the family history.  

Neuropathology

Neuropathological data are unavailable, but amyloid deposition was detected by F18-florbetaben-PET in frontal areas, the parietal lobes, and the precunei of the Italian woman, consistent with her mixed disease phenotype (Scarioni et al., 2020). Cerebrospinal fluid levels of Aβ42 and tau were consistent with AD in both Italian patients.

MRI scans showed mild parietal atrophy in the Italian woman (Scarioni et al., 2020) and frontotemporal atrophy in the Italian man (Borroni et al., 2011). In addition, FDG-PET revealed frontotemporal  hypometabolism without significant parietal involvement in the man and, in the woman, bilateral hypometabolism, more marked on the the right hemisphere, in the precuneus, posterior cingulum, inferior parietal lobes, temporal, and frontal lobes.

Biological Effect

An in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate revealed it dramatically reduces Aβ42 production and abrogates Aβ40 production (Sun et al., 2017). Consistent with these findings, in silico analyses predicted this mutation is likely to have a pathological effect on protein function. Moreover, a cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates that R377 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 APP cleavage (Zhou et al., 2019; Jan 2019 news). In addition, the mutation may affect splicing since the nucleotide forms part of a splice site (Borroni et al., 2011). 

Last Updated: 11 Sep 2020

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References

News Citations

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

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. . 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.
  3. . Atypical presentation of a novel Presenilin 1 R377W mutation: sporadic, late-onset Alzheimer disease with epilepsy and frontotemporal atrophy. Neurol Sci. 2011 Aug 6; PubMed.
  4. . Late-onset presentation and phenotypic heterogeneity of the rare R377W PSEN1 mutation. Eur J Neurol. 2020 Sep 7; 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.
  6. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 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. . Atypical presentation of a novel Presenilin 1 R377W mutation: sporadic, late-onset Alzheimer disease with epilepsy and frontotemporal atrophy. Neurol Sci. 2011 Aug 6; PubMed.

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