Mutations

PSEN1 M233I (G>C)

Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PS1, PS2, PS3, PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73659502 G>C
dbSNP ID: rs63751479
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: ATG to ATC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This mutation was detected in a patient with neuropathologically confirmed Alzheimer's disease (Portet et al., 2003). At age 28, the patient began to experience memory problems that affected activities of daily living. Her disease progressed quickly, with worsening memory and language impairments and stereotyped and perseverative behavior. By age 31, pyramidal signs were present, associated with a cerebellar syndrome, rigidity, and myoclonic jerking. She continued to deteriorate, becoming immobile, incontinent, and mute, with swallowing difficulties and generalized tonic-clonic seizures. She died at age 36.

The parents of the proband were unaffected and did not carry the mutation. Paternity was confirmed by microsatellite typing, therefore the mutation is thought to have arisen de novo in the proband. The mutation was absent in 50 unrelated control subjects. To note, the mutation was erroneously reported as M233L.

The variant was absent from the gnomAD variant database (v2.1.1, Nov 2022).

Neuropathology

A right frontal brain biopsy showed pathology consistent with a diagnosis of AD, including amyloid plaques and tau-positive neurofibrillary tangles. Astrocytic gliosis, spongiosis, and prion disease were not observed (Portet et al., 2003). A subsequent report, including data from apparently the same carrier, described diffuse cerebral amyloid angiopathy and hippocampal atrophy as revealed by an MRI scan taken 2.7 years after symptom onset (Lacour et al., 2019).

Biological Effect

Two in-depth studies of the Aβ peptides produced by cells transfected with M233I (nucleotide change unspecified) revealed a deleterious effect, decreasing both the Aβ (37 + 38 + 40) / (42 + 43) and Aβ37/Aβ42 ratios compared with cells expressing wildtype PSEN1 (Apr 2022 news; Petit et al., 2022; Liu et al., 2022). Both ratios were reported to outperform the Aβ42/Aβ40 ratio as indicators of AD pathogenicity, with the former correlating with AD age at onset.

A cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates that, in wild-type PSEN1, 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).

Although some in silico algorithms to predict the effects of this variant on protein function yielded conflicting results (Xiao et al., 2021), the CADD-PHRED tool, which integrates diverse information, gave it a high deleteriousness score above 20 (CADD v.1.6, Sep 2021).

The variant was classified as definitely pathogenic (Wallon et al., 2012) according to the algorithm proposed by Guerreiro et al., 2010.

Pathogenicity

Alzheimer's Disease : Not Classified*

*This variant fulfilled some ACMG-AMP criteria, but it was not classified by Alzforum, because data for either a pathogenic or benign classification are lacking: only one affected carrier has been reported without co-segregation data, and the variant is absent—or very rare—in the gnomAD database.

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

PS1-S

Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.

PS2-S

De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.

PS3-S

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.

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. M233I (G>C): 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.

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: 18 Nov 2022

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References

News Citations

  1. Ratio of Short to Long Aβ Peptides: Better Handle on Alzheimer's than Aβ42/40?
  2. CryoEM γ-Secretase Structures Nail APP, Notch Binding

Paper Citations

  1. . Very early onset AD with a de novo mutation in the presenilin 1 gene (Met 233 Leu). Neurology. 2003 Oct 28;61(8):1136-7. PubMed.
  2. . Causative Mutations and Genetic Risk Factors in Sporadic Early Onset Alzheimer's Disease Before 51 Years. J Alzheimers Dis. 2019;71(1):227-243. PubMed.
  3. . Aβ profiles generated by Alzheimer's disease causing PSEN1 variants determine the pathogenicity of the mutation and predict age at disease onset. Mol Psychiatry. 2022 Jun;27(6):2821-2832. Epub 2022 Apr 1 PubMed.
  4. . Identification of the Aβ37/42 peptide ratio in CSF as an improved Aβ biomarker for Alzheimer's disease. Alzheimers Dement. 2022 Mar 12; PubMed.
  5. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
  6. . APP, PSEN1, and PSEN2 Variants in Alzheimer's Disease: Systematic Re-evaluation According to ACMG Guidelines. Front Aging Neurosci. 2021;13:695808. Epub 2021 Jun 18 PubMed.
  7. . The French series of autosomal dominant early onset Alzheimer's disease cases: mutation spectrum and cerebrospinal fluid biomarkers. J Alzheimers Dis. 2012 Jan 1;30(4):847-56. PubMed.
  8. . Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP. Neurobiol Aging. 2010 May;31(5):725-31. Epub 2008 Jul 30 PubMed.

External Citations

  1. CADD v.1.6

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Very early onset AD with a de novo mutation in the presenilin 1 gene (Met 233 Leu). Neurology. 2003 Oct 28;61(8):1136-7. PubMed.

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