Mutations

PSEN1 Y288H

Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PM1, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease, Dementia, Parkinsonism, Spastic Paraparesis
Reference Assembly: GRCh37/hg19
Position: Chr14:73664831 T>C
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: TAC to CAC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

This variant was identified in a family presenting with early onset dementia (Wicklund et al, 2013). Three family members suffered from spastic paraparesis, progressive cognitive decline, and parkinsonism. Two others developed cognitive impairment in their 30s, with one case preceded by seizures. The variant was identified in the proband, but it is unclear if other family members were genotyped. A subsequent report (Joseph-Mathurin et al., 2021) referred to this variant as associated with dominantly inherited Alzheimer's disease (AD), although an AD diagnosis was not reported in the original study.

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

Neuropathology
Neuropathological data are unavailable, but the proband had increased levels of Aβ42 and an elevated Aβ42/Aβ40 ratio in serum (Wicklund et al, 2013). Moreover, 25 percent of individuals carrying this variant had more than five cerebral microhemorrhages per year, with the most severe case having more than nine (Joseph-Mathurin et al., 2021).

Biological Effect
The biological effect of this variant is unknown, but the abnormal levels of Aβ42 and the elevated Aβ42/Aβ40 ratio in serum noted above suggest an effect on APP processing (Wicklund et al, 2013). Moreover, the CADD-PHRED tool, which integrates diverse information, gave it a high deleteriousness score, above 20 (CADD v.1.6, Sep 2021).

According to a cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment, Y288 is one of three amino acids in PSEN1 (287-290) which, upon APP binding, forms a β1 strand that becomes part of a hybrid β-sheet composed of residues from both proteins (Zhou et al., 2019; Jan 2019 news). Deletion of PSEN1 residues 288 to 290 crippled the proteolytic cleavage of an APP fragment.

Pathogenicity

Alzheimer's Disease : Not Classified*

*This variant fulfilled some ACMG-AMP criteria, but it is not classified by Alzforum because the number of affected carriers, evidence of cosegregation, and evidence of functional effects were unavailable.

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. Y288H : 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.

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: 22 Feb 2022

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References

News Citations

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

Paper Citations

  1. . Familial Dementia, Parkinsonism, Seizures and Spastic Paraparesis Associated with the Novel Y288H Presenilin-1 Mutation (PD5.008) (poster abstract). Neurology, February 8, 2016
  2. . Longitudinal Accumulation of Cerebral Microhemorrhages in Dominantly Inherited Alzheimer Disease. Neurology. 2021 Mar 23;96(12):e1632-e1645. Epub 2021 Jan 25 PubMed.
  3. . 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

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