Mutations

PSEN1 F388S

Overview

Pathogenicity: Alzheimer's Disease : Likely Pathogenic
Clinical Phenotype: Alzheimer's Disease, Spastic Paraparesis
Reference Assembly: GRCh37/hg19
Position: Chr14:73683867 T>C
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: TTC to TCC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 11

Findings

This variant was identified in several members of a family who experienced the first symptoms of Alzheimer’s disease with spastic paraparesis at an unusually young age (Ringman et al., 2019). The proband, a woman originally from El Salvador, began having trouble walking at around age 24. She then developed dementia and dysphagia. Four of her seven children have developed similar symptoms with a similar age at onset. As assessed by whole-exome sequencing, the proband and an affected 27 year-old son carried the variant, but an unaffected 28 year-old daughter did not, indicating co-segregation of the variant with the disease.

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

Neuropathology
Neuropathological data are unavailable, but MRI brain imaging revealed atrophy in the brainstem (Ringman et al., 2019). Moreover, diffusion tensor imaging, used to identify microstructural pathology associated with spastic paraparesis, showed abnormalities in corticospinal tracts compared with controls.

Biological Effect
The biological effect of this mutation is unknown, but an in silico algorithm (Polyphen) predicted it is probably damaging (Ringman et al., 2019) and its PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, Oct 2021). A cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates that F388 helps form a shallow hydrophobic pocket for part of the C-terminal portion of the APP transmembrane helix (Zhou et al., 2019; Jan 2019 news).

Last Updated: 12 Oct 2021

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References

News Citations

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

Paper Citations

  1. . P1-123: VERY YOUNG ONSET AUTOSOMAL DOMINANT ALZHEIMER'S DISEASE WITH SPASTIC PARAPARESIS DUE TO A NOVEL (F388S) PSEN1 MUTATION (poster abstract). Alzheimer's & Dementia, July 1, 2019
  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. . P1-123: VERY YOUNG ONSET AUTOSOMAL DOMINANT ALZHEIMER'S DISEASE WITH SPASTIC PARAPARESIS DUE TO A NOVEL (F388S) PSEN1 MUTATION (poster abstract). Alzheimer's & Dementia, July 1, 2019

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