Mutations

PSEN1 I416T

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73683951 T>C
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: ATT to ACT
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 12

Findings

This mutation was identified in a clinical and genetic evaluation of 93 related individuals from a Colombian admixed population (Ramirez Aguilar et al., 2019). The mutation was found to segregate with AD (LOD score of 6). More than a third of the participants (26) were identified as carriers of the mutation. Eight older healthy controls (>55 years) did not carry the variant, and it was absent from more than 200,000 healthy individuals in population databases. The associated clinical phenotype is similar to sporadic AD except for earlier age at onset (mean of 47.6 years for MCI and 51.6 years for dementia).

Interestingly, genotypic analyses of the haplotype structure around the mutation indicated the variant occurs on a haplotypic backgound of African origin. The authors note the history of the region includes immigration from Africa in the 17th century as a result of slavery, and admixtures within a confined geographic locale, likely representing a “mini-population bottleneck” and subsequent emergence of a rare dominant mutation. 

Neuropathology
Although neuropathological data are unavailable, PET-amyloid and PET-tau scans of two cognitively normal mutation carriers revealed evidence of preclinical amyloid plaques and tau accumulation similar to those reported for individuals at risk for late-onset AD and individuals carrying other AD-causing PSEN1 mutations.

Biological effect
The I416T mutation affects a highly conserved residue in the eighth transmembrane domain of PSEN1, resulting in the substitution of a hydrophobic amino acid with a polar amino acid near a splice site. Computational algorithms, including SIFT, PolyPhen2 HDIV and HVAR, MutationTaster, FATHMM, MetaSVM, PROVEAN, and REVEL, predict the mutation is deleterious. Moreover, because the variant co-segregated with disease in three or more cases within the Colombian family, it was classified as definitely pathogenic according to the Guerreiro algorithm (Guerreiro et al., 2010). 

Last Updated: 14 Feb 2019

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References

Paper Citations

  1. . Genetic origin of a large family with a novel PSEN1 mutation (Ile416Thr). Alzheimers Dement. 2019 May;15(5):709-719. Epub 2019 Feb 10 PubMed.
  2. . 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.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Genetic origin of a large family with a novel PSEN1 mutation (Ile416Thr). Alzheimers Dement. 2019 May;15(5):709-719. Epub 2019 Feb 10 PubMed.

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