Mutations

PSEN1 V191A

Overview

Pathogenicity: Alzheimer's Disease : Unclear Pathogenicity
Clinical Phenotype: None
Reference Assembly: GRCh37 (105)
Position: Chr14:73659375 T>C
dbSNP ID: rs112451138
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GTT to GCT
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This mutation was found in an individual from the African San population (Guerreiro et al. 2010).  No neurodegenerative phenotype was reported. It was absent from two exome variant databases, EVS and ExAC (Hsu et al., 2020).

Neuropathology
Unknown

Biological effect
Mouse neuroblastoma cells expressing this variant secreted approximately half the amount of Aβ42 as cells expressing wild-type PSEN1 (Hsu et al., 2020). Secretion of Aβ40 was also decreased, but this reduction did not reach significance, nor did reduction in the Aβ42/Aβ40 ratio.

The V191 position is conserved between PSEN1 and PSEN2, and the substitution to alanine was predicted to be possibly damaging by Polyphen in silico analysis, and tolerated by SIFT. Hsu et al. classified the mutation as not pathogenic and possibly protective.

Last Updated: 01 Sep 2020

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References

Paper Citations

  1. Guerreiro RJ, Baquero M, Blesa R, Boada M, Brás JM, Bullido MJ, Calado A, Crook R, Ferreira C, Frank A, Gómez-Isla T, Hernández I, Lleó A, Machado A, Martínez-Lage P, Masdeu J, Molina-Porcel L, Molinuevo JL, Pastor P, Pérez-Tur J, Relvas R, Oliveira CR, Ribeiro MH, Rogaeva E, Sa A, Samaranch L, Sánchez-Valle R, Santana I, Tàrraga L, Valdivieso F, Singleton A, Hardy J, Clarimón J. 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.
  2. Hsu S, Pimenova AA, Hayes K, Villa JA, Rosene MJ, Jere M, Goate AM, Karch CM. Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2. Neurobiol Dis. 2020 Jun;139:104817. Epub 2020 Feb 19 PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. Guerreiro RJ, Baquero M, Blesa R, Boada M, Brás JM, Bullido MJ, Calado A, Crook R, Ferreira C, Frank A, Gómez-Isla T, Hernández I, Lleó A, Machado A, Martínez-Lage P, Masdeu J, Molina-Porcel L, Molinuevo JL, Pastor P, Pérez-Tur J, Relvas R, Oliveira CR, Ribeiro MH, Rogaeva E, Sa A, Samaranch L, Sánchez-Valle R, Santana I, Tàrraga L, Valdivieso F, Singleton A, Hardy J, Clarimón J. 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.

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