Mutations

PSEN1 T116_P117delinsST

Overview

Pathogenicity: Alzheimer's Disease : Not Classified
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73640281_73640284 ACCC>TCTA
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Insertion/Deletion
Codon Change: ACC CCA to TCT ACA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 5

Findings

This mutation was identified in a Spanish family with nine members affected by AD, spanning five generations (Blanco et al., 2019). The proband was a 37-year-old man admitted to a psychiatric ward with multiple cognitive impairments, including disorientation, visual hallucinations, speech alterations, severe memory loss, as well as visuospatial and praxis deficits.  He also had a history of thalassemia minor and migraine headaches, and presented with mild bradykinesia, hyperreflexia, and a tendency to swerve left when walking. His unaffected sister reported he had been suffering progressive cognitive decline during the last two years.

Descriptions provided by family members of the other eight affected individuals, together with clinical records from four of these patients, revealed they all developed similar symptoms during their 30s. In addition, two of the clinical records reported spastic paraparesis, and the other two noted ataxic gait and myoclonus.  The mutation was found in the proband and an affected uncle. It was absent from the gnomAD variant database (gnomAD v2.1.1, August 2021).

Neuropathology
Brain biopsies from two patients showed neurofibrillary tangles and neuritic plaques consistent with AD. Also, levels of AD biomarkers in the proband's cerebrospinal fluid, including Aβ42, total tau, and phosphorylated tau, were typical of AD.

An MRI scan of the proband’s brain revealed white matter lesions and diffuse cortical atrophy, while SPECT showed frontoparietal hypoperfusion, mainly of the right hemisphere. A CT scan of another affected family member revealed severe cortical and subcortical atrophy.

Biological Effect
This mutation substitutes the T116 codon, ACC, and the first C of the P117 codon for TCTA resulting in the replacement of T116 with a serine and P117 with a threonine. Both T116 and P117 have been identified as key for PSEN1's γ-processivity, the carboxypeptidase activity that trims Aβ intermediates to form shorter, secreted species (Liu et al., 2021).

In silico algorithms to predict the effects of this variant on protein function (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve) yielded conflicting results (Blanco et al., 2019Xiao et al., 2021). PredictSNP categorized the T116S substitution as neutral, and P117T as pathogenic (Blanco et al., 2019).

Last Updated: 13 Sep 2021

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

Paper Citations

  1. . Novel presenilin 1 mutation (p.Thr-Pro116-117Ser-Thr) in a Spanish family with early-onset Alzheimer's disease. Neurobiol Aging. 2019 May 20; PubMed.
  2. . 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 Jan-Jun;296:100393. Epub 2021 Feb 8 PubMed.
  3. . 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. . Novel presenilin 1 mutation (p.Thr-Pro116-117Ser-Thr) in a Spanish family with early-onset Alzheimer's disease. Neurobiol Aging. 2019 May 20; PubMed.

Other mutations at this position

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.