Mutations

PSEN1 L166del

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73653575 GCTT>G
dbSNP ID: rs63751458
Coding/Non-Coding: Coding
Mutation Type: Deletion
Codon Change: CTT to ---
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 6

Findings

This deletion of three nucleotides (one amino acid) was detected in a woman who developed insidious onset of memory impairment at age 38 (Knight et al., 2007). Her general short-term memory was affected and the report noted particular difficulties with topographical memory (the ability to navigate around a familiar environment) as well as in the ability to comprehend numbers and arithmetic. She did not have myoclonus or extrapyramidal signs. Her mother had died at the age of 46 with dementia, after suffering from progressive memory impairment from an unknown age. The patient's father had a diagnosis of vascular dementia at age 83 years. Segregation with disease could not be assessed as DNA was available only from the patient; however, it was noted that the deletion was absent in 100 normal controls.

Neuropathology

Unknown. MRI showed generalized, symmetrical cerebral atrophy, which was most prominent in the medial temporal lobes (Knight et al., 2007).

Biological Effect

In an in vitro assay with isolated proteins, this mutant produced less Aβ42 than wild-type PSEN1, and Aβ40 production was undetectable (Sun et al., 2017). A cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates this residue is apposed to the APP transmembrane helix, with its side-chain reaching towards the interior of the substrate-binding pore (Zhou et al., 2019; Jan 2019 news).

Last Updated: 13 Aug 2019

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References

News Citations

  1. CryoEM γ-Secretase Structures Nail APP, Notch Binding

Paper Citations

  1. . A novel presenilin 1 deletion (p.L166del) associated with early onset familial Alzheimer's disease. Eur J Neurol. 2007 Jul;14(7):829-31. 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. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.

Further Reading

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Protein Diagram

Primary Papers

  1. . A novel presenilin 1 deletion (p.L166del) associated with early onset familial Alzheimer's disease. Eur J Neurol. 2007 Jul;14(7):829-31. PubMed.

Other mutations at this position

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