Mutations

PSEN1 I238_K239insI

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73659518 ->TAA
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Insertion
Codon Change: AAG to ATAAAG
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. 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.

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. In silico PROVEAN software predictes this insertion is deleterious.

Last Updated: 18 Sep 2015

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References

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Further Reading

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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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