Mutations

PSEN1 I143T

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM5, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease, Myoclonus
Reference Assembly: GRCh37/hg19
Position: Chr14:73640363 T>C
dbSNP ID: rs63750004
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: ATT to ACT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 5

Findings

This mutation has been found in several families worldwide, and in at least two, segregation with Alzheimer's disease was demonstrated. It was first identified by linkage analysis in a large Belgian family affected by early onset Alzheimer’s disease (Cruts et al., 1995). The family, known as AD/A, included at least 31 affected individuals over six generations, many of whom had neuropathologically confirmed AD. The mean age at onset in this family was 35 years.

This mutation was also found in three other individuals with early onset AD. Of these mutation carriers, two were sisters who also carried a second PSEN1 mutation in trans. They both inherited the I143T mutation from their father and the PSEN1 I439V mutation from their mother, who was asymptomatic at age 55. The sisters both developed symptoms before age 35 (Rogaeva et al., 2001). The mutation was also reported in a Colombian family of Western European ancestry with very early onset, autosomal dominant AD (Arango et al., 2001).

Several French carriers have also been reported. A family, known as ROU 001, included at least three individuals affected by early onset AD. Symptom onset occurred at age 34 or 35. Note, the mutation was erroneously reported as I143W (Raux et al., 2005). A subsequent report described two additional French carriers from different families, whose AD onset also occurred in their mid-30s (Lanoiselée et al., 2017). One of these carriers had paraperesis, in addition to typical AD symptoms (Lacour et al., 2019).

Two Japanese sisters with early onset AD also carried the mutation (Arai et al., 2008). One became unable to communicate at age 33, followed by gradual memory decline. Five years later, she also had apraxia, agnosia, alexia, acalculia, and developed limb rigidity, dystonia, and myoclonus. Her APOE genotype was E3/E4. Her sister presented with memory impairment and time disorientation at age 41. She was homozygous for the APOE3 allele.

In a Swedish family, with three mutation carriers, five family members across three generations were affected with early onset dementia (Keller et al., 2010). The mean age of onset was 36 and mean age of death 42. Initial symptoms were typical of AD, including memory impairment, visuospatial difficulties, disorientation, dyspraxia, and dysphasia. In addition, patients presented with gradually worsening myoclonic jerks, multiple falls, and, in some cases, epileptic seizures. In the later stages of disease, paranoid delusions, hallucinations, and aggressiveness developed and, in the first generation, Pick's disease was suspected based on observed personality changes. The tree affected mutation carriers were APOE3 homozygotes. A 24-year-old study of this family includes prospective assessments of cognitive function, tissue sampling, and brain imaging of presymptomatic, at-risk individuals (Thordardottir and Graff, 2018).

The mutation was also found in a Chinese woman with memory impairment starting at age 30 (Xu et al., 2018). She developed emotional instability, tremor of an arm, and visual hallucinations. Her father and grandmother experienced similar symptoms at similar ages.

This mutation is absent from the gnomAD variant database (gnomAD v2.1.1, May 2021).

Neuropathology

Autopsies were performed on at least 11 affected family members from the AD/A family. Neuropathology consistent with the diagnosis of AD was observed, including amyloid plaques and neurofibrillary tangles in the cortex. A few cerebellar plaques were also noted (Martin et al., 1991).

Severe AD pathology was also reported in the three Swedish mutations carriers (Keller et al., 2010). The frontal lobes were particularly affected by the thinning of gyri and the reduced cortical thickness, with a large number of plaques observed, often lacking a distinct core. Tau pathology, including numerous ghost tangles, was widespread and severe in the hippocampal areas, entorhinal cortex, and amygdala. Superficial spongiform changes and gliosis were present. Some neurons in the granular cell layer of the dentate gyrus had phosphorylated tau. The cerebellum was clearly affected by amyloid in two cases. In these same cases, Aβ42 and Aβ43 were found in both plaque cores and total amyloid preparations, and were each more frequent than Aβ40.

One carrier was reported to have Lewy body pathology limited to the amygdala, as assessed by α-synuclein staining (Leverenz et al., 2020). 

Cerebrospinal fluid biomarkers including Aβ42, tau, and phospho-tau were consistent with AD in at least one case (Lanoiselée et al., 2017). This individual had diffuse cortical atrophy as assessed by MRI, and bilateral temporo-pariteal hypometabolism as assessed by PET/SPECT imaging (Lacour et al., 2019).

Biological Effect

In vitro this mutation has been shown to increase the Aβ42/Aβ total ratio when expressed in COS-1 cells co-transfected with APP695 (Murayama et al., 1999). When transfected into HEK293 cells stably expressing Swedish mtAPP695 and BACE1, this mutation impaired the carboxypeptidase-like γ-cleavage, but spared the endoproteolytic ε-cleavage activity of PSEN1. This resulted in reduced secreted Aβ40, increased Aβ42, and an increased Aβ42/Aβ40 ratio (Li et al., 2016). Consistent with these findings, another cell-based assay showed an increase in Aβ42 and a decrease in Aβ40 and Aβ38 production (Kakuda et al., 2021). Of note, Aβ43 production was reduced compared with control cells but slightly increased when normalized to total Aβ production. Analyses of the short peptides generated from the stepwise processing of Aβ suggested Aβ43 may be generated from Aβ48 in several AD-associated mutants, rather than the canonical Aβ49 precusor. Interestingly, increased Aβ43 levels and increased production by the alternate Aβ48 pathway correlated with younger ages at disease onset.

An in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate also revealed an increased Aβ42/Aβ40 ratio (nearly 20-fold), but showed reductions in the production of both Aβ40 and Aβ42 peptides compared with wild-type PSEN1 (Sun et al., 2017).

A cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates that, in wild-type PSEN1, this residue is apposed to the APP transmembrane helix, with its side-chain reaching towards the interior of the substrate-binding pore (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.

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. I143T: 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.

PM5-M

Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.

PP1-S

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. I143T: Cosegregation demonstrated in >1 family.

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)

Last Updated: 05 Mar 2022

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References

News Citations

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

Paper Citations

  1. . Molecular genetic analysis of familial early-onset Alzheimer's disease linked to chromosome 14q24.3. Hum Mol Genet. 1995 Dec;4(12):2363-71. PubMed.
  2. . Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.
  3. . Systematic genetic study of Alzheimer disease in Latin America: mutation frequencies of the amyloid beta precursor protein and presenilin genes in Colombia. Am J Med Genet. 2001 Oct 1;103(2):138-43. PubMed.
  4. . Molecular diagnosis of autosomal dominant early onset Alzheimer's disease: an update. J Med Genet. 2005 Oct;42(10):793-5. Epub 2005 Jul 20 PubMed.
  5. . 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.
  6. . Causative Mutations and Genetic Risk Factors in Sporadic Early Onset Alzheimer's Disease Before 51 Years. J Alzheimers Dis. 2019;71(1):227-243. PubMed.
  7. . Familial cases presenting very early onset autosomal dominant Alzheimer's disease with I143T in presenilin-1 gene: implication for genotype-phenotype correlation. Neurogenetics. 2008 Feb;9(1):65-7. Epub 2007 Oct 30 PubMed.
  8. . The PSEN1 I143T mutation in a Swedish family with Alzheimer's disease: clinical report and quantification of Aβ in different brain regions. Eur J Hum Genet. 2010 Nov;18(11):1202-8. PubMed.
  9. . Findings from the Swedish Study on Familial Alzheimer's Disease Including the APP Swedish Double Mutation. J Alzheimers Dis. 2018;64(s1):S491-S496. PubMed.
  10. . The Whole Exome Sequencing Clarifies the Genotype- Phenotype Correlations in Patients with Early-Onset Dementia. Aging Dis. 2018 Aug;9(4):696-705. PubMed.
  11. . Early-onset Alzheimer's disease in 2 large Belgian families. Neurology. 1991 Jan;41(1):62-8. PubMed.
  12. . Lewy body pathology in familial Alzheimer disease: evidence for disease- and mutation-specific pathologic phenotype. Arch Neurol. 2006 Mar;63(3):370-6. PubMed.
  13. . Enhancement of amyloid beta 42 secretion by 28 different presenilin 1 mutations of familial Alzheimer's disease. Neurosci Lett. 1999 Apr 9;265(1):61-3. PubMed.
  14. . Effect of Presenilin Mutations on APP Cleavage; Insights into the Pathogenesis of FAD. Front Aging Neurosci. 2016;8:51. Epub 2016 Mar 11 PubMed.
  15. . Switched Aβ43 generation in familial Alzheimer's disease with presenilin 1 mutation. Transl Psychiatry. 2021 Nov 3;11(1):558. PubMed.
  16. . 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.
  17. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
  18. . 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. PSEN1 I439V

External Citations

  1. gnomAD v2.1.1

Further Reading

Papers

  1. . Predicting Cognitive Decline across Four Decades in Mutation Carriers and Non-carriers in Autosomal-Dominant Alzheimer's Disease. J Int Neuropsychol Soc. 2017 Mar;23(3):195-203. Epub 2017 Jan 12 PubMed.
  2. . Preclinical cerebrospinal fluid and volumetric magnetic resonance imaging biomarkers in Swedish familial Alzheimer's disease. J Alzheimers Dis. 2015;43(4):1393-402. PubMed.

Protein Diagram

Primary Papers

  1. . Molecular genetic analysis of familial early-onset Alzheimer's disease linked to chromosome 14q24.3. Hum Mol Genet. 1995 Dec;4(12):2363-71. PubMed.
  2. . Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.

Other mutations at this position

Alzpedia

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