Mutations

PSEN1 S290W;S291_R377del (Δ9-10 )

Overview

Pathogenicity: Early-onset : Pathogenic
Clinical Phenotype: Alzheimer's Disease, Spastic Paraparesis
Coding/Non-Coding: Both
Mutation Type: Deletion
Genomic Region: Introns 8-10, Exons 9-10

Findings

This mutation involves the deletion of 10.1 kilobases between introns 8 and 10 (g.73671948_73682054del) and results in the in-frame removal of exons 9 and 10. Even though the deletion is in-frame, a S290W missense mutation is predicted at the junction between exons 8 and 11.

This particular mutation was identified in a French patient in a cohort of 546 unrelated patients of French ancestry who were diagnosed with early onset Alzheimer’s disease. At age 56, the proband developed progressive cognitive decline, including deficits in declarative memory and executive function. He also had symptoms of spasticity, similar to other patients lacking exon 9 for PSEN1. The proband’s mother had a history of dementia, with symptom onset at age 50 and death 10 years later. No other family members were available for genetic testing (Le Guennec et al., 2017).

CSF biomarkers were available from the proband showing that total tau and phosphorylated tau were elevated, while Aβ42 levels were decreased. Structural imaging revealed atrophy in the medial temporal lobe and in the occipital-parietal cortex.

The Δ9-10 deletion was absent from 597 controls.

Biological Effect

Analysis of patient mRNA extracted from peripheral blood cells showed transcripts lacking exons 9 and 10 were expressed at the same level as the wild-type allele. To examine the biological effect of the loss of exons 9 and 10, either wild-type presenilin or Δ9-10 were expressed in PSEN1/2 knockout MEF cells. In this context, the Δ9-10 construct was still able to bind other members of the γ-secretase complex to constitute the holo-enzyme. Cells expressing Δ9-10, however, exhibited severe deficits in endopeptidase and carboxypeptidase activity, resulting in an overall decrease in production of Aβ peptides. While Aβ42, Aβ40, and Aβ38 peptides were decreased, Aβ43 fragments were greatly increased, consistent with other pathogenic PSEN1 mutations (Le Guennec et al., 2017).

Last Updated: 04 Jun 2019

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References

Paper Citations

  1. . Deletion of exons 9 and 10 of the Presenilin 1 gene in a patient with Early-onset Alzheimer Disease generates longer amyloid seeds. Neurobiol Dis. 2017 Aug;104:97-103. Epub 2017 Apr 28 PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Deletion of exons 9 and 10 of the Presenilin 1 gene in a patient with Early-onset Alzheimer Disease generates longer amyloid seeds. Neurobiol Dis. 2017 Aug;104:97-103. Epub 2017 Apr 28 PubMed.
  2. . APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases. PLoS Med. 2017 Mar;14(3):e1002270. Epub 2017 Mar 28 PubMed.

Other mutations at this position

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