Mutations

PSEN1 T116N

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM5, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73173574 C>A
Position: (GRCh37/hg19):Chr14:73640282 C>A
dbSNP ID: rs63750730
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: ACC to AAC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 5

Findings

This mutation was first reported in a Danish family with four affected individuals over three generations. The mutation was observed to segregate with early onset Alzheimer’s disease in an autosomal dominant manner. Age at onset in the four known affected individuals ranged from 35 to 41 years (mean: 38 years). Progression was rapid in this family, with duration from symptom onset to death averaging 5.7 years (range: four to eight years). The clinical diagnosis of AD was confirmed at autopsy in one family member (Romero et al., 1999).

The T116N mutation was subsequently detected in two other kindreds. In the family known as ALZ 157, there were four affected family members, whose age of onset ranged from 30 to 33 years (Raux et al., 2005). Most recently, the mutation was found in a Slovak family with five affected family members in three generations (Sutovsky et al., 2018). Age of onset in this family was in the third or fourth decade, and ages at death ranged from 32 to 44 years. A detailed clinical description was available for the proband, whose symptoms included progressive memory impairment, amnestic aphasia, and gait disturbances; MRI showed mediotemporal atrophy. The proband was found to carry the T116N mutation, while three unaffected siblings, all over age 50, did not. DNA was not available from other affected family members.

This mutation was also found in three additional unrelated patients with AD. Clinical details were not available in the first patient (Rogaeva et al., 2001). The second patient experienced symptom onset at age 37 (Guerreiro et al, 2010). The third patient presented at age 38, at which time he fulfilled criteria for mild cognitive impairment; MRI at this time revealed mild atrophy of the parietal cortex and no hippocampal volume loss (Smith et al., 2016). Cognition in this patient continued to deteriorate, and MRI at age 43 showed generalized cortical atrophy, most pronounced in parietal lobes, mild hippocampal atrophy, and enlarged lateral ventricles. Amyloid-PET (18F-Flutemetamol) showed increased tracer uptake in neocortex; tau-PET (18F-AV1451) showed highest uptake in posterior cingulate, precuneus, and parietal and occipital cortices; FDG-PET showed hypometabolism in a pattern the inverse of that seen with the tau tracer.

The variant was absent from the gnomAD variant database (gnomAD v2.1.1, May 2021).

Neuropathology

A detailed neuropathological description is available for the proband in the Slovak family (Sutovsky et al., 2018). At autopsy, severe atrophy of all lobes was observed, and AD neuropathology was graded as Thal stage 5 and Braak stage 6. Cotton-wool plaques, present in all cortical areas and in the basal forebrain, were most abundant in the occipital cortex, which also contained the highest number of neuritic plaques. Many amyloid plaques surrounded cortical neurons. Neurofibrillary tangles and neuropil threads were abundant in cortex, hippocampus, striatum, basal forebrain and thalamus. In the cerebellum, amyloid deposits were primarily perivascular, and neurofibrillary tangles were absent.

Neuropathology consistent with a diagnosis of AD was found in another mutation carrier (Romero et al., 1999). Moreover, PET imaging data from yet another individual was also consistent with AD (Smith et al., 2016). However, while amyloid accumulation was similar to that seen in sporadic AD, tau pathology was increased in the posterior cingulate, precuneus, and the parietal and occipital cortices compared with late-onset, sporadic AD. Regions with tau accumulation correlated with hypometabolism as assessed by FDG-PET.

Biological Effect

This mutant appears to reduce γ-processivity (Liu et al., 2021). Analysis of secreted Aβs in the conditioned media of human embryonic kidney cells lacking endogenous PSENs and expressing this mutant along with wildtype APP, revealed increased Aβ42/40 ratio and decreased Aβ37/40, Aβ37/42, and Aβ38/42 ratios. Interestingly, the authors also reported that Aβ42/40, Aβ38/42, and particularly Aβ37/42, ratios each correlated with reported ages of onset of clinical impairment across 16 PSEN1 mutations. This mutant also reduced total secreted Aβ levels.

Consistently, an in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate revealed it reduces production of both Aβ40 and Aβ42 peptides, and increases the Aβ42/Aβ40 ratio approximately three-fold (Sun et al., 2017).

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-M

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.

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. T116N: 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: 22 Feb 2022

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

Paper Citations

  1. . A presenilin-1 Thr116Asn substitution in a family with early-onset Alzheimer's disease. Neuroreport. 1999 Aug 2;10(11):2255-60. PubMed.
  2. . 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.
  3. . Neuropathology and biochemistry of early onset familial Alzheimer's disease caused by presenilin-1 missense mutation Thr116Asn. J Neural Transm (Vienna). 2018 Jun;125(6):965-976. Epub 2018 Feb 5 PubMed.
  4. . Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.
  5. . 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.
  6. . Posterior Accumulation of Tau and Concordant Hypometabolism in an Early-Onset Alzheimer's Disease Patient with Presenilin-1 Mutation. J Alzheimers Dis. 2016;51(2):339-43. PubMed.
  7. . Hydrophilic loop 1 of Presenilin-1 and the APP GxxxG transmembrane motif regulate γ-secretase function in generating Alzheimer-causing Aβ peptides. J Biol Chem. 2021;296:100393. Epub 2021 Feb 8 PubMed.
  8. . 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.
  9. . 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

No Available Further Reading

Protein Diagram

Primary Papers

  1. . A presenilin-1 Thr116Asn substitution in a family with early-onset Alzheimer's disease. Neuroreport. 1999 Aug 2;10(11):2255-60. PubMed.

Other mutations at this position

Alzpedia

Disclaimer: Alzforum does not provide medical advice. The Content is for informational, educational, research and reference purposes only and is not intended to substitute for professional medical advice, diagnosis or treatment. Always seek advice from a qualified physician or health care professional about any medical concern, and do not disregard professional medical advice because of anything you may read on Alzforum.