Mutations

PSEN1 T116N

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73640282 C>A
dbSNP ID: rs63750730
Coding/Non-Coding: Coding
Mutation Type: Point, 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.

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

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

Last Updated: 11 Sep 2019

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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. . 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.

Further Reading

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

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.

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