Mutations

PSEN1 F388S

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PM1, PM2, PM5, PP1, PP2, PP3
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).

Pathogenicity

Alzheimer's Disease : Pathogenic

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

PM1-S

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. F388S: Variant is in a mutational hot spot and cryo-EM data suggest residue is of functional importance.

PM2-M

Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. *Alzforum uses the gnomAD variant database.

PM5-M

Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.

PP1-M

Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease: *Alzforum requires at least one affected carrier and one unaffected non-carrier from the same family to fulfill this criterion. F388S: At least one family with 2 affected carriers and >=1 unaffected noncarriers.

PP2-P

Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.

PP3-P

Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). *In most cases, Alzforum applies this criterion when the variant’s PHRED-scaled CADD score is greater than or equal to 20.

Pathogenic (PS, PM, PP) Benign (BA, BS, BP)
Criteria Weighting Strong (-S) Moderate (-M) Supporting (-P) Supporting (-P) Strong (-S) Strongest (BA)

Last Updated: 15 Aug 2022

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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

Papers

  1. . Abnormal retinal capillary blood flow in autosomal dominant Alzheimer's disease. Alzheimers Dement (Amst). 2021;13(1):e12162. Epub 2021 Mar 4 PubMed.

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

Other mutations at this position

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