Mutations

PSEN1 Y156F; Y156_R157insIY

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease, Spastic Paraparesis
Reference Assembly: GRCh37 (105)
Position: Chr14:73640401 T>TTTATAT
dbSNP ID: rs63750631
Coding/Non-Coding: Coding
Mutation Type: Insertion
Codon Change: TAC to TTT.ATA.TAC
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 5

Findings

This mutation is a six-nucleotide insertion (TTATAT) predicted to result in a missense substitution at codon 156 (Y156F), and an insertion of an isoleucine and tyrosine immediately after codon 156. It was found in a screen for variants in the open reading frame of the PSEN1 gene in participants from the U.S., Germany, and Canada who had been referred for AD diagnostic testing (Rogaeva et al., 2001). The cohort included 372 patients with AD and 42 asymptomatic individuals with a strong family history of AD.
Symptoms and neuropathology were subsequently described for two carriers of the mutation in a Michigan family with five affected individuals spanning four generations (Moretti et al., 2004). The disease was characterized by very early onset (28 years of age in the proband), rapidly progressing dementia, and early presentation of spastic paraparesis, dystonia, and motor speech changes. Like typical AD, patients developed cognitive problems first.

Neuropathology
Neuropathology in one case was typical of AD, but more severe and widespread. Classic AD plaques, as well as cotton-wool plaques, were present in neocortex, limbic regions, and to a lesser extent, the striatum. Moreover, sequential FDG-PET scans from two individuals revealed rapidly progressing hypo-metabolism starting in the posterior temporo-parietal cortex, and subsequently spreading to other areas, including the posterior cingulate, primary motor, and frontal association cortices (Moretti et al., 2004).

Biological Effect
The biological effects of this mutation are unknown. Codon 156 is in a highly conserved region of the PSEN1 gene.

Last Updated: 05 Apr 2019

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References

Paper Citations

  1. . Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.
  2. . Novel insertional presenilin 1 mutation causing Alzheimer disease with spastic paraparesis. Neurology. 2004 May 25;62(10):1865-8. PubMed.

Further Reading

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Protein Diagram

Primary Papers

  1. . Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.
  2. . Novel insertional presenilin 1 mutation causing Alzheimer disease with spastic paraparesis. Neurology. 2004 May 25;62(10):1865-8. PubMed.

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