Mutations

PSEN1 L166H

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73653577 T>A
dbSNP ID: rs63750265
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: CTT to CAT
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 6

Findings

This mutation was identified in an Italian woman who began to experience progressive memory loss at age 30. She did not have a strong family history of dementia. Notably, her parents did not show signs of dementia before their deaths at age 63 and 83 years, and her grandparents and five older siblings were likewise unaffected. A brother and a sister of her paternal grandparents were both affected by late-onset dementia, but no further details were available. In addition to cognitive impairment, the patient developed extrapyramidal signs, myoclonus, postural tremor, and persistent blinking. Segregation with disease could not be determined as only the patient's DNA was analyzed; however, it was noted that the mutation was absent in 95 unrelated healthy Italian subjects (Pantieri et al., 2005).

Neuropathology

Unknown. MRI showed marked hippocampal atrophy and cortical atrophy, especially in the insula and the peri-insular temporal lobe. SPECT imaging showed bilateral hypometabolism in the parietal and frontal lobes.

Biological Effect

Unknown. 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 L166H mutation in a pseudo-sporadic case of early-onset Alzheimer's disease. Neurol Sci. 2005 Dec;26(5):349-50. PubMed.
  2. . 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 L166H mutation in a pseudo-sporadic case of early-onset Alzheimer's disease. Neurol Sci. 2005 Dec;26(5):349-50. PubMed.

Other mutations at this position

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