Mutations

PSEN1 V261F

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic, Spastic Paraparesis : Pathogenic, Cerebral Amyloid Angiopathy : Pathogenic
Clinical Phenotype: Spastic Paraparesis, Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73664750 G>T
dbSNP ID: rs63750964
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GTT to TTT
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

This mutation was found in a kindred in which affected members had both spasticity and dementia (Farlow et al., 2000). The proband first developed progressive stiffening in his legs at age 38 and subsequently suffered from impaired short-term memory, ability to do calculations, and executive function at age 42. At this stage, brain MRI, visual evoked potentials, and lower extremity nerve conduction were normal. Across a span of three years, the proband became wheelchair-bound and deeply demented. His father, sister, and a paternal aunt developed similar symptoms and died in their 40s. The proband and two affected siblings were shown to carry the mutation which was absent from 120 normal controls.

The mutation was also found in a screen for variants in the open reading frame of the PSEN1 gene in participants from the U.S., Germany, and Canada who had been referred for AD diagnostic testing (Rogaeva et al., 2001). The cohort included 372 patients with AD and 42 asymptomatic individuals with a strong family history of AD.

Neuropathology
Neuropathology was consistent with AD and included cotton-wool plaques and severe cerebral amyloid angiopathy involving the leptomeninges, cerebral, and cerebellar parenchyma (Farlow et al., 2000; Albrecht et al., 2009). In addition, degeneration of the lateral pyramidal tracts was seen in the spinal cord.

Biological Effect
In vitro experiments using the APP C99 substrate, showed the mutant protein produced less Aβ42 and Aβ40 than wild-type PSEN1, and increased the Aβ42/Aβ40 ratio approximately five-fold (Bai et al., 2015; Sun et al., 2017). In addition, the mutant nearly abrogated autoproteolysis.

Last Updated: 19 Sep 2019

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

Paper Citations

  1. . Hereditary lateral sclerosis and Alzheimer disease associated with mutation at codon 261 of the presenilin 1 (PS1) gene. Neurobiol Aging. 2000 May-Jun; 21(Suppl 1):62.
  2. . Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.
  3. . Caspase-6 activation in familial alzheimer disease brains carrying amyloid precursor protein or presenilin i or presenilin II mutations. J Neuropathol Exp Neurol. 2009 Dec;68(12):1282-93. PubMed.
  4. . An atomic structure of human γ-secretase. Nature. 2015 Sep 10;525(7568):212-7. Epub 2015 Aug 17 PubMed.
  5. . Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase. Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E476-E485. Epub 2016 Dec 5 PubMed.

Further Reading

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Protein Diagram

Primary Papers

  1. . Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.
  2. . Hereditary lateral sclerosis and Alzheimer disease associated with mutation at codon 261 of the presenilin 1 (PS1) gene. Neurobiol Aging. 2000 May-Jun; 21(Suppl 1):62.
  3. . Familial Alzheimer's disease with spastic paraparesis associated with a mutation at codon 261 of the presenilin 1 gene. In: Alzheimer's Disease: Advances in Etiology, Pathogenesis and Therapeutics. 2001. Chapter 6. pp53-60.

Other mutations at this position

Alzpedia

Disclaimer: Alzforum does not provide medical advice. The Content is for informational, educational, research and reference purposes only and is not intended to substitute for professional medical advice, diagnosis or treatment. Always seek advice from a qualified physician or health care professional about any medical concern, and do not disregard professional medical advice because of anything you may read on Alzforum.