Mutations

PSEN1 I238_K239insI

Overview

Pathogenicity: Alzheimer's Disease : Not Classified
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73659518_73659519 --->TAA
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Insertion
Codon Change: --- to TAA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This mutation, involving the insertion of three nucleotides (TAA), was identified in a young man with cognitive decline initially attributed to Korsakoff syndrome due to a history of chronic alcohol dependency (Roeber et al., 2015). It is unclear at what age his symptoms started, but by age 35 his executive functioning was severely impaired. In addition, he exhibited a variety of motor symptoms including dysphagia, myoclonus, gait problems, and spastic tetraparesis. He also developed seizures. His disease was apparently sporadic.

This variant was absent from the gnomAD variant database (gnomAD v2.1.1, July 2021).

Neuropathology

Cerebral MRI showed generalized cortical and subcortical atrophy. Postmortem examination revealed cortical atrophy, mainly of the frontal lobe. Neuropathology consistent with AD was documented (Braak and Braak stage VI, CERAD C). Specifically, numerous neurofibrillary tangles and amyloid plaques were observed, as well as ghost tangles, neuropil threads, and neuritic plaques. Cerebral amyloid angiopathy was also present.

Biological Effect

Unknown. This mutation, involving the insertion of the trinucleotide TAA, results in the insertion of one amino acid (isoleucine), but does not cause a frameshift. Several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve) predicted this variant is damaging (Xiao et al., 2021).

Last Updated: 11 Sep 2021

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References

Paper Citations

  1. . Three novel presenilin 1 mutations marking the wide spectrum of age at onset and clinical patterns in familial Alzheimer's disease. J Neural Transm (Vienna). 2015 Dec;122(12):1715-9. Epub 2015 Sep 8 PubMed.
  2. . 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. . Three novel presenilin 1 mutations marking the wide spectrum of age at onset and clinical patterns in familial Alzheimer's disease. J Neural Transm (Vienna). 2015 Dec;122(12):1715-9. Epub 2015 Sep 8 PubMed.

Other mutations at this position

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