Mutations

PSEN1 T116S; P117T

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
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.

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.  In silico algorithms, including PolyPhen2, SIFT, and PROVEAN, classified the mutation as deleterious or pathogenic. However, Mutation Taster 2 described it as a variant of “uncertain significance” and Mutation Assessor predicted it would have a “medium” effect on function. Moreover, PredictSNP categorized the T116S substitution as neutral, and P117T as pathogenic.

Last Updated: 06 Sep 2019

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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.

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

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