Mutations

PSEN1 R278I

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic, Progressive Nonfluent Aphasia : Not Classified
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease, Progressive Nonfluent Aphasia
Reference Assembly: GRCh37/hg19
Position: Chr14:73664802 G>T
dbSNP ID: rs63749891
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: AGA to ATA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 8
Research Models: 1

Findings

This variant has been identified in several individuals with variable clinical phenotypes. It was first detected in two siblings in the U.K. from a pedigree with four affected members over three generations (Godbolt et al., 2004). In both cases, the disease was characterized by early language impairment with relative preservation of episodic memory. Specifically, one family member presented with word-finding difficulty and speech impairment at the age of 48. Over the next eight years her condition deteriorated and she developed mutism, rigidity, myoclonus of the upper limbs, and a shuffling gait. She was diagnosed with progressive nonfluent aphasia (PNFA). Her brother developed symptoms at age 51. He also had word-finding difficulties along with impairments in other executive functions. His disease, described as an atypical clinical syndrome, was suspected to be an atypical presentation of Alzheimer's disease (AD). In a subsequent study from the same research group, the authors listed this mutation as associated with autosomal dominant AD, and reported that out of five affected carriers, behavioral symptoms were observed in one, language impairment in two, myoclonus in three, spastic paraperesis in two, and extrapyramidal signs in three individuals (Ryan et al., 2016).

The mutation was also found in a Korean family with dementia in which the proband was diagnosed with multiple domain amnestic mild cognitive impairment at age 49 (Kim et al., 2020). The man reported forgetfulness emerging approximately 10 years prior. His father developed dementia in his early 60s and his brother, a mutation carrier, developed dementia in his early 50s. His sisters, in their 50s, and his elderly mother had normal cognition. The DNA of one of the sisters and the mother were sequenced revealing the mother was not a carrier, but the asymptomatic sister, age 55 or 58, was. 

Neuropathology

Post-mortem analyses of two British carriers revealed neuropathology consistent with AD (Willumsen et al., 2021). Interestingly, one of them, who had an APOE3/4 genotype, had markedly more Aβ pathology than the other who had an APOE2/3 genotype. The former also had larger plaques and a greater extent of amyloid deposition, particularly in cortical layer 3, as well as greater cerebral amyloid angiopathy in the cortex and subpial deposition. Both carriers had α-synuclein pathology in the amygdala, with the APOE2/3 carrier also showing TDP-43 pathology in this region. 

MRI scans of the two British siblings who were first identified and the Korean proband showed no or minimal brain atrophy (Godbolt et al., 2004; Kim et al., 2020). The British individuals had multiple white matter-foci, however. In addition, a flutemetamol-PET scan revealed amyloid deposition in the cerebral cortex of the Korean carrier.

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

Biological Effect

In vitro, this mutation severely impairs endoproteolysis of presenilin-1 and causes a selective increase in secreted Aβ43, an aggregating and neurotoxic peptide, and an increase in the Aβ42/Aβ40 ratio (Nakaya et al., 2005, Saito et al., 2011, July 2011 newsSzaruga et al., 2015).  In knock-in mice, Aβ43 generated extensive plaques (Saito et al., 2011). Consistently, the mutant produced about 30 percent less Aβ42 and than wild-type PSEN1, and more Aβ43 than Aβ42, in transfected mouse embryonic fibroblasts (Veugelen et al., 2016; April 2016 news). Moreover, assays using purified PSEN1 complexes and a tagged APPC99 substrate revealed it is more sensitive to increased temperatures, suggesting the mutation destabilizes the interaction required for proteolysis of APPC99 and newly produced Aβn substrates, resulting in the release of longer Aβ peptides (Szaruga et al., 2017). 

Subsequent experiments analyzing the Aβ peptidome of neurons derived from two patient induced pluripotent stem cell (iPSC) lines, indicated this mutant moderately increases Aβ42/Aβ40 and Aβ42/Aβ38 ratios, and more robustly increases the Aβ43/Aβ40 ratio (Arber et al., 2019; see April 2019 news). The Aβ38/Aβ40 ratio remained unchanged. The elevated ratios suggest inefficient carboxypeptidase activity, predisposing neurons to accumulate longer Aβ fragments. Western blot analyses revelead impaired autocatalysis required for PSEN1 maturation. 

Cross-linking experiments revealed that the interaction between the mutant and the Aβ peptide precursor C99 is disrupted, with a robust reduction at the major contact point, V44, and increased crosslinking at K54 (Trambauer et al., 2020). Moreover, a cryo-electron microscopy study of the atomic structure of γ-secretase bound to a shorter APP fragment, C83, suggests R278 plays a key role in stabilizing the hybrid β-sheet that forms between PSEN1 and APP in preparation for cleavage (Zhou et al., 2019; Jan 2019 news).

The variant’s effects on γ-secretase substrates beyond APP may also have pathogenic consequences. One study showed R278I impaired the processing of ApoER2, a member of the low-density lipoprotein receptor family that binds ApoE and has been implicated in long-term potentiation and neuronal migration (Wang et al., 2017). Moreover, R278I likely also affects the processing of Notch, a protein involved in neuronal differentiation. Premature neurogenesis was observed during the differentiation of induced pluripotent stem cells harboring the mutation in a 2D model of cortical differentiation, as well as in the generation of a 3D cerebral organoid (Arber et al., 2021). Also, examination of adult hippocampal neurogenesis in post-mortem tissue revealed a trend toward reduced abundance of newborn neurons, possibly indicating a premature aging phenotype. 

Additional damaging effects have been reported. A study using co-cultures of neurons and astrocytes derived from patient iPSCs revealed a decrease in the expression of ADAM10, an enzyme involved in the non-amyloidogenic processing of APP, as well as a shift in cellular redox status (Elsworthy et al., 2021). 

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.

PS3-S

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.

PM1-S

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. R278I: Variant is in a mutational hot spot and cryo-EM data suggest residue is of functional importance.

PM2-M

Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. *Alzforum uses the gnomAD variant database.

PP1-M

Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease: *Alzforum requires at least one affected carrier and one unaffected non-carrier from the same family to fulfill this criterion. R278I: At least one family with 2 affected carriers and >=1 unaffected noncarriers.

PP2-P

Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.

PP3-P

Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). *In most cases, Alzforum applies this criterion when the variant’s PHRED-scaled CADD score is greater than or equal to 20.

Pathogenic (PS, PM, PP) Benign (BA, BS, BP)
Criteria Weighting Strong (-S) Moderate (-M) Supporting (-P) Supporting (-P) Strong (-S) Strongest (BA)

Research Models

A knock-in mouse model expressing human presenilin-1 with the R278I mutation has been generated. As a homozygote it is embryonic lethal due to impaired endoproteolysis of presenilin-1 and loss of γ-secretase functioning. Heterozygous mice are viable and overproduce Aβ43. When crossed to an APP transgenic model, APP23, double mutants developed high levels of Aβ43 and accelerated amyloid pathology (Saito et al., 2011).

Last Updated: 28 Feb 2022

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References

Research Models Citations

  1. APP23

News Citations

  1. What’s Another Amino Acid? Aβ43 Drives Amyloid Pathology
  2. Pathogenic Presenilin Mutations Generate Aβ43
  3. Familial Alzheimer’s Mutations: Different Mechanisms, Same End Result
  4. CryoEM γ-Secretase Structures Nail APP, Notch Binding

Paper Citations

  1. . Potent amyloidogenicity and pathogenicity of Aβ43. Nat Neurosci. 2011 Aug;14(8):1023-32. PubMed.
  2. . A presenilin 1 R278I mutation presenting with language impairment. Neurology. 2004 Nov 9;63(9):1702-4. PubMed.
  3. . Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer's disease: a case series. Lancet Neurol. 2016 Dec;15(13):1326-1335. Epub 2016 Oct 21 PubMed.
  4. . The R278I Mutation of PSEN1 in the Familial Alzheimer Disease. Dement Neurocogn Disord. 2020 Mar;19(1):33-35. Epub 2020 Feb 25 PubMed.
  5. . Variability in the type and layer distribution of cortical Aβ pathology in familial Alzheimer's disease. Brain Pathol. 2021 Jul 28;:e13009. PubMed.
  6. . Random mutagenesis of presenilin-1 identifies novel mutants exclusively generating long amyloid beta-peptides. J Biol Chem. 2005 May 13;280(19):19070-7. PubMed.
  7. . Qualitative changes in human γ-secretase underlie familial Alzheimer's disease. J Exp Med. 2015 Nov 16;212(12):2003-13. Epub 2015 Oct 19 PubMed.
  8. . Familial Alzheimer's Disease Mutations in Presenilin Generate Amyloidogenic Aβ Peptide Seeds. Neuron. 2016 Apr 20;90(2):410-6. PubMed.
  9. . Alzheimer's-Causing Mutations Shift Aβ Length by Destabilizing γ-Secretase-Aβn Interactions. Cell. 2017 Jul 27;170(3):443-456.e14. PubMed.
  10. . Familial Alzheimer's disease patient-derived neurons reveal distinct mutation-specific effects on amyloid beta. Mol Psychiatry. 2019 Apr 12; PubMed.
  11. . Aβ43-producing PS1 FAD mutants cause altered substrate interactions and respond to γ-secretase modulation. EMBO Rep. 2020 Jan 7;21(1):e47996. Epub 2019 Nov 25 PubMed.
  12. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
  13. . Presenilin 1 mutations influence processing and trafficking of the ApoE receptor apoER2. Neurobiol Aging. 2017 Jan;49:145-153. Epub 2016 Oct 11 PubMed.
  14. . Familial Alzheimer's Disease Mutations in PSEN1 Lead to Premature Human Stem Cell Neurogenesis. Cell Rep. 2021 Jan 12;34(2):108615. PubMed.
  15. . Amyloid-β precursor protein processing and oxidative stress are altered in human iPSC-derived neuron and astrocyte co-cultures carrying presenillin-1 gene mutations following spontaneous differentiation. Mol Cell Neurosci. 2021 Jul;114:103631. Epub 2021 May 20 PubMed.
  16. . 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.

External Citations

  1. gnomAD v2.1.1

Further Reading

Protein Diagram

Primary Papers

  1. . A presenilin 1 R278I mutation presenting with language impairment. Neurology. 2004 Nov 9;63(9):1702-4. PubMed.

Other mutations at this position

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