Overview

Pathogenicity: Alzheimer's Disease : Likely Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PS4, PM1, PM2, PM4, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73211942 A>T
Position: (GRCh37/hg19):Chr14:73678650 A>T
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Splicing Alteration
Expected Protein Consequence: Deletion; Missense
Codon Change: AGG to TGG
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 10

Findings

This mutation, which affects the splicing of PSEN1 mRNA and results in a truncated protein, has been reported in four 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.  

A 55 year-old Italian man with apparent cerebral amyloid angiopathy (CAA) and cognitive decline was also found to carry this variant, together with another PSEN1 variant, S357Ter (Palmieri et al., 2021). His condition was diagnosed as multiple domain amnestic mild cognitive impairment complicated by movement disorders with probable CAA. Progression to AD was not confirmed.

This variant was absent from the gnomAD variant database (gnomAD v2.1.1, August 2021).

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.

Moreover, an MRI scan of the Italian patient with the two PSEN1 variants revealed multifocal subcortical microhemorrhages mainly in the left posterior hemisphere (Palmieri et al., 2021).

Biological Effect

The affected nucleotide of this variant is the last nucleotide of exon 10, forming part of a splice site (Borroni et al., 2011). Consistently, RNA analyses revealed aberrant splicing resulting in retention of 43 intronic nucleotides and a frameshift with the predicted incorporation of a stop codon after 32 amino acids, creating a protein 59 amino acids shorter than the wild-type (Palmieri et al., 2021). The insertion did not always occur, however, suggesting a small fraction of translated protein includes the R377W substitution.

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). Moreover, multiple in silico analyses predicted this mutation is likely to have a pathological effect on protein function (Xiao et al., 2021). In addition, 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). Three-dimensional modeling using Raptor X predicted a slight alteration in structure caused by R377W (Palmieri et al., 2021).

Pathogenicity

Alzheimer's Disease : Likely Pathogenic

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

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References

Mutations Citations

1. PSEN1 S357Ter

News Citations

1. CryoEM γ-Secretase Structures Nail APP, Notch Binding 11 Jan 2019

Paper Citations

1. Wallon D, Rousseau S, Rovelet-Lecrux A, Quillard-Muraine M, Guyant-Maréchal L, Martinaud O, Pariente J, Puel M, Rollin-Sillaire A, Pasquier F, Le Ber I, Sarazin M, Croisile B, Boutoleau-Bretonnière C, Thomas-Antérion C, Paquet C, Moreaud O, Gabelle A, Sellal F, Sauvée M, Laquerrière A, Duyckaerts C, Delisle MB, Streichenberger N, Lannes B, Frebourg T, Hannequin D, Campion D. 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. Guerreiro RJ, Baquero M, Blesa R, Boada M, Brás JM, Bullido MJ, Calado A, Crook R, Ferreira C, Frank A, Gómez-Isla T, Hernández I, Lleó A, Machado A, Martínez-Lage P, Masdeu J, Molina-Porcel L, Molinuevo JL, Pastor P, Pérez-Tur J, Relvas R, Oliveira CR, Ribeiro MH, Rogaeva E, Sa A, Samaranch L, Sánchez-Valle R, Santana I, Tàrraga L, Valdivieso F, Singleton A, Hardy J, Clarimón J. 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. Borroni B, Pilotto A, Bonvicini C, Archetti S, Alberici A, Lupi A, Gennarelli M, Padovani A. 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. Scarioni M, Arighi A, Fenoglio C, Sorrentino F, Serpente M, Rotondo E, Mercurio M, Marotta G, Dijkstra AA, Pijnenburg YA, Scarpini E, Galimberti D. Late-onset presentation and phenotypic heterogeneity of the rare R377W PSEN1 mutation. Eur J Neurol. 2020 Dec;27(12):2630-2634. Epub 2020 Oct 12 PubMed.
5. Palmieri I, Valente M, Farina LM, Gana S, Minafra B, Zangaglia R, Pansarasa O, Sproviero D, Costa A, Pacchetti C, Pichiecchio A, Gagliardi S, Cereda C. PSEN1 Compound Heterozygous Mutations Associated with Cerebral Amyloid Angiopathy and Cognitive Decline Phenotype. Int J Mol Sci. 2021 Apr 8;22(8) PubMed.
6. Sun L, Zhou R, Yang G, Shi Y. 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.
7. Xiao X, Liu H, Liu X, Zhang W, Zhang S, Jiao B. APP, PSEN1, and PSEN2 Variants in Alzheimer's Disease: Systematic Re-evaluation According to ACMG Guidelines. Front Aging Neurosci. 2021;13:695808. Epub 2021 Jun 18 PubMed.
8. Zhou R, Yang G, Guo X, Zhou Q, Lei J, Shi Y. Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.

External Citations

1. gnomAD v2.1.1

Further Reading

No Available Further Reading