Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PS4, PM1, PM2, PM5, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease, Cerebral Amyloid Angiopathy
Position: (GRCh38/hg38):Chr14:73217129 G>A
Position: (GRCh37/hg19):Chr14:73683837 G>A
dbSNP ID: rs63750323
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GGA to GAA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 11

Findings

The G378E mutation has been detected in families of European, Japanese, and Chinese ancestry. It is associated with a clinical presentation typical for early onset Alzheimer’s disease (AD), although atypical presentations have also been reported. 

Several studies of French AD cohorts have reported this mutation (Besançon et al., 1998, Zarea et al., 2016, Lanoiselée et al., 2017). The initial report was of a French pedigree that included four affected individuals over three generations (Besançon et al., 1998). The proband first developed symptoms at age 34, beginning as memory impairment, but rapidly expanding to other cognitive domains. The mean age at onset in the family was 35 years with a mean age at death of 39 years. The mutation segregated with disease in this family. It was present in two affected individuals and two at-risk individuals who were below the mean onset age, but it was absent in a healthy family member aged 69. It was also absent in 50 unrelated controls. In a subsequent study, this mutation was identified  in a screen of patients with early onset AD from 28 French hospitals (Lanoiselée et al., 2017). Families were included when at least two first-degree relatives, spanning two generations, suffered from early onset AD with an age of onset of 65 years or younger. In this family, age at onset ranged from 38 to 44 years with a disease duration ranging from six to nine years. Atypical symptoms were reported in the single mutation carrier examined, including cerebellar ataxia and extrapyramidal syndrome. The carrier was homozygous for the APOE3 allele.

This mutation was also found in two purportedly unrelated German patients with early onset AD, reported as p.53 and p.44. Patient p.53 developed dementia in his 30s and died at age 52 with autopsy-confirmed AD. His mother died at age 39 with dementia. Patient p.44 was diagnosed with AD at age 42, onset age unknown. Her brother and mother were also affected, and both died at age 43 (Finckh et al., 2005).

In addition, the mutation was identified in a family of Western European ancestry from a Brazilian cohort of families with at least two first-degree relatives diagnosed with early onset AD in two generations (Takada et al., 2017, Llibre-Guerra et al., 2020). The predominant symptoms were memory loss and behavioral alterations, and the mean age at onset was 33.7 years with a range of 35-44.

Moreover, a Japanese pedigree reported as P283 included two affected individuals over two generations. The average age at onset in this family was 40 years and the proband met NINCDS-ADRDA criteria for probable AD. The proband was noted to have a clinical phenotype typical of AD, principally characterized by progressive memory loss. Segregation with disease could not be assessed due to lack of DNA from family members other than the proband. No mutations in APP, PSEN2, or MAPT were detected in the proband and the mutation was absent from 100 chromosomes of healthy Japanese people (Ikeuchi et al., 2008).

In addition, the mutation was reported in six of 17 members of a Chinese family. Five of the mutation carriers were diagnosed with dementia, while one was clinically normal, but under onset age. The mutation was absent in 10 patients with sporadic AD and 100 healthy subjects (Cao et al., 2014).

The mutation is absent from the ExAC variant database (Lanoiselée et al., 2017).

Neuropathology

Neuropathological analysis of one affected family member from each of the French and German families revealed neuropathology consistent with AD. The German case also had notable cerebral amyloid angiopathy (CAA) (Finckh et al., 2005; Besançon et al., 1998).

Biological Effect

When co-expressed in HEK-293 expressing human APP with the Swedish mutation, the mutant presenilin-1 was associated with elevated secreted Aβ42 and an elevated Aβ42/Aβ40 ratio compared with cells expressing wild-type presenilin-1 (Ikeuchi et al., 2008). Consistent with this finding, an in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate revealed increased Aβ42 and decreased Aβ40 production, with a corresponding increase in the Aβ42/Aβ40 ratio (Sun et al., 2017). The mutation did not appear to affect γ-secretase cleavage of Notch, as NICD production was unchanged (Ikeuchi et al., 2008).

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).

Several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) predicted this variant is damaging (Xiao et al., 2021).

Pathogenicity

Alzheimer's Disease : 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

News Citations

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

Paper Citations

1. Besançon R, Lorenzi A, Cruts M, Radawiec S, Sturtz F, Broussolle E, Chazot G, van Broeckhoven C, Chamba G, Vandenberghe A. Missense mutation in exon 11 (Codon 378) of the presenilin-1 gene in a French family with early-onset Alzheimer's disease and transmission study by mismatch enhanced allele specific amplification. Mutations in brief no. 141. Online. besancon@rockefeller1. Hum Mutat. 1998;11(6):481. PubMed.
2. Zarea A, Charbonnier C, Rovelet-Lecrux A, Nicolas G, Rousseau S, Borden A, Pariente J, Le Ber I, Pasquier F, Formaglio M, Martinaud O, Rollin-Sillaire A, Sarazin M, Croisile B, Boutoleau-Bretonnière C, Ceccaldi M, Gabelle A, Chamard L, Blanc F, Sellal F, Paquet C, Campion D, Hannequin D, Wallon D, PHRC GMAJ Collaborators. Seizures in dominantly inherited Alzheimer disease. Neurology. 2016 Aug 30;87(9):912-9. Epub 2016 Jul 27 PubMed.
3. Lanoiselée HM, Nicolas G, Wallon D, Rovelet-Lecrux A, Lacour M, Rousseau S, Richard AC, Pasquier F, Rollin-Sillaire A, Martinaud O, Quillard-Muraine M, de la Sayette V, Boutoleau-Bretonniere C, Etcharry-Bouyx F, Chauviré V, Sarazin M, le Ber I, Epelbaum S, Jonveaux T, Rouaud O, Ceccaldi M, Félician O, Godefroy O, Formaglio M, Croisile B, Auriacombe S, Chamard L, Vincent JL, Sauvée M, Marelli-Tosi C, Gabelle A, Ozsancak C, Pariente J, Paquet C, Hannequin D, Campion D, collaborators of the CNR-MAJ project. APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases. PLoS Med. 2017 Mar;14(3):e1002270. Epub 2017 Mar 28 PubMed.
4. Finckh U, Kuschel C, Anagnostouli M, Patsouris E, Pantes GV, Gatzonis S, Kapaki E, Davaki P, Lamszus K, Stavrou D, Gal A. Novel mutations and repeated findings of mutations in familial Alzheimer disease. Neurogenetics. 2005 May;6(2):85-9. Epub 2005 Mar 18 PubMed.
5. Takada LT, Brucki SM, Rodriguez RD, Smid J, Bahia VS, Chadi G, Nitrini R. Autosomal Dominant Early-Onset Alzheimer's Disease: Characterization of a Brazilian Cohort . Alzheimer's & Dementia, July 2017
6. Llibre-Guerra JJ, Li Y, Allegri RF, Mendez PC, Surace EI, Llibre-Rodriguez JJ, Sosa AL, Aláez-Verson C, Longoria EM, Tellez A, Carrillo-Sánchez K, Flores-Lagunes LL, Sánchez V, Takada LT, Nitrini R, Ferreira-Frota NA, Benevides-Lima J, Lopera F, Ramírez L, Jiménez-Velázquez I, Schenk C, Acosta D, Behrens MI, Doering M, Ziegemeier E, Morris JC, McDade E, Bateman RJ. Dominantly inherited Alzheimer's disease in Latin America: Genetic heterogeneity and clinical phenotypes. Alzheimers Dement. 2021 Apr;17(4):653-664. Epub 2020 Nov 23 PubMed.
7. Ikeuchi T, Kaneko H, Miyashita A, Nozaki H, Kasuga K, Tsukie T, Tsuchiya M, Imamura T, Ishizu H, Aoki K, Ishikawa A, Onodera O, Kuwano R, Nishizawa M. Mutational analysis in early-onset familial dementia in the Japanese population. The role of PSEN1 and MAPT R406W mutations. Dement Geriatr Cogn Disord. 2008;26(1):43-9. Epub 2008 Jun 28 PubMed.
8. Cao L, Qiu X, Zheng J, Lin P, Wang S. [Study of mutations of presenilin 1 gene in early-onset familial Alzheimers disease]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2014 Jun;31(3):298-301. PubMed.
9. 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.
10. 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.
11. 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.

Other Citations

1. Swedish mutation

Further Reading