Mutations

PSEN1 V151M

Overview

Pathogenicity: Alzheimer's Disease : Not Classified
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73640386 G>A
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 5

Findings

This variant was identified in a man diagnosed with Alzheimer’s disease from a large cohort study in South China in which 14 genes associated with neurodegenerative dementias from 1795 patients were sequenced (Jiao et al., 2021). His age at onset was 49 years and his APOE genotype was APOE E3/E4. He had a family history of AD. The clinical phenotypes reported included memory loss, language impairment, and mental and behavioral changes.

This variant was absent from the gnomAD variant database (gnomAD v2.1.1, Sep 2021).

Neuropathology
Unknown.

Biological Effect
The biological effect of this variant is unknown, but in silico analyses predicted a damaging effect with a PHRED-scaled CADD score above 20 (CADD v.1.6, Sep 2021). As revealed by a cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment, V151 appears to help stabilize the hybrid β-sheet that forms between PSEN1 and APP in preparation for cleavage (Zhou et al., 2019; Jan 2019 news).

Last Updated: 13 Oct 2021

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References

News Citations

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

Paper Citations

  1. . The role of genetics in neurodegenerative dementia: a large cohort study in South China. NPJ Genom Med. 2021 Aug 13;6(1):69. PubMed.
  2. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.

External Citations

  1. gnomAD v2.1.1
  2. CADD v.1.6

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . The role of genetics in neurodegenerative dementia: a large cohort study in South China. NPJ Genom Med. 2021 Aug 13;6(1):69. PubMed.

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