Mutations

PSEN1 L134R

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73640336 T>G
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: CTG to CGG
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 5

Findings

This mutation was detected in a Turkish man with a family history of Alzheimer’s disease. The proband developed symptoms at age 53, starting with memory impairment. His disease progressed rapidly, and he developed mood lability, disorientation, visual hallucinations, and spasticity in his legs. He was bedridden by age 55 and died four years after onset.

At least four members of this family (AD-46) were affected by AD. Transmission was consistent with autosomal dominant inheritance; however, segregation with disease could not be determined due to lack of DNA from family members (Lohmann et al., 2012).

Neuropathology

Unknown. MRI of the Turkish proband showed atrophy of the cerebrum and cerebellum (Lohmann et al., 2012).

Biological Effect

An in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate revealed decreased production of Aβ42, and no detectable production of Aβ40 (Sun et al., 2017). In silico, this mutation is predicted probably damaging by PolyPhen-2. It has been classified as possibly pathogenic according to the algorithm proposed by Guerreiro et al., 2010 (Lohmann et al., 2012).

Last Updated: 18 Sep 2019

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References

Paper Citations

  1. . Identification of PSEN1 and PSEN2 gene mutations and variants in Turkish dementia patients. Neurobiol Aging. 2012 Aug;33(8):1850.e17-27. PubMed.
  2. . Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase. Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E476-E485. Epub 2016 Dec 5 PubMed.
  3. . Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP. Neurobiol Aging. 2010 May;31(5):725-31. Epub 2008 Jul 30 PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Identification of PSEN1 and PSEN2 gene mutations and variants in Turkish dementia patients. Neurobiol Aging. 2012 Aug;33(8):1850.e17-27. PubMed.

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