Mutations

PSEN1 R352_S353insR

Overview

Pathogenicity: Frontotemporal Dementia : Unclear Pathogenicity
Clinical Phenotype: Frontotemporal Dementia
Reference Assembly: GRCh37 (105)
Position: Chr14:73678576 CGC>---
dbSNP ID: rs63750762
Coding/Non-Coding: Coding
Mutation Type: Insertion
Codon Change: CGC.TCT to CGC.CGC.TCT
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 10

Findings

This variant was identified in a kindred with three cases of dementia, in which the proband had symptoms typical of frontotemporal dementia and parkinsonism (FTDP). Upon the proband's death at age 63, neuropathologic examination revealed frontotemporal lobar degeneration (FTLD) with ubiquitin-positive inclusions. Analysis of the progranulin gene identified a G to A mutation in the exon 1 splice donor site (IVS1+1G-->A) predicted to destroy the 5'-splice site of exon 1 and completely block progranulin production. Thus, the effects of this PSEN1 mutation remain unknown and may be non-pathogenic (Boeve et al., 2006). In a subsequent study, the variant was described as most likely having reduced penetrance, with an allele count of four, and a frequency of 0.0014 percent in the gnomAD variant database (Koriath et al., 2018).

Biological effect
The mutation is an in-frame insertion of 3 nucleotides in exon 10 resulting in the addition of an arginine between amino acids R352 and S353. Aβ CSF and plasma levels in the proband were roughly normal (Tang-Wai et al., 2002). In cultured cells, expression of the mutation increased the Aβ42:Aβ40 ratio, but markedly reduced the levels of both secreted Aβ40 and Aβ42 (Amtul et al., 2002).

Last Updated: 22 Jul 2019

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References

Paper Citations

  1. . Frontotemporal dementia and parkinsonism associated with the IVS1+1G->A mutation in progranulin: a clinicopathologic study. Brain. 2006 Nov;129(Pt 11):3103-14. PubMed.
  2. . Predictors for a dementia gene mutation based on gene-panel next-generation sequencing of a large dementia referral series. Mol Psychiatry. 2018 Oct 2; PubMed.
  3. . Familial frontotemporal dementia associated with a novel presenilin-1 mutation. Dement Geriatr Cogn Disord. 2002;14(1):13-21. PubMed.
  4. . A presenilin 1 mutation associated with familial frontotemporal dementia inhibits gamma-secretase cleavage of APP and notch. Neurobiol Dis. 2002 Mar;9(2):269-73. PubMed.

Further Reading

Papers

  1. . Mutations in progranulin explain atypical phenotypes with variants in MAPT. Brain. 2006 Nov;129(Pt 11):3124-6. PubMed.

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. . Familial frontotemporal dementia associated with a novel presenilin-1 mutation. Dement Geriatr Cogn Disord. 2002;14(1):13-21. PubMed.
  3. . A presenilin 1 mutation associated with familial frontotemporal dementia inhibits gamma-secretase cleavage of APP and notch. Neurobiol Dis. 2002 Mar;9(2):269-73. PubMed.

Other mutations at this position

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