Mutations

PSEN1 T119I

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73640291 C>T
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: ACA to ATA
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 5

Findings

This variant was found in an Argentine family of Italian descent, spanning four generations, with 13 individuals affected by autosomal dominant AD (Itzcovich et al., 2019). Age of onset varied widely (49-71), with a median of 56. The mutation was present in the proband, an affected cousin, and a sibling whose neuropsychological profile was unavailable. It was absent from three of the proband’s children who had no cognitive complaints, but had yet to reach the median age of onset (43 to 54 years old). The mutation was also reported in a Korean woman with early onset AD and an unknown family history of the disease (Giau et al., 2019). Memory loss was the first symptom, surfacing at 64 years of age, followed by continued memory decline, language impairment, and personality changes. She was homozygous for the APOE 3 allele. The mutation was absent from the gnomAD, Exome Variant Server, and ExAC variant databases.

Neuropathology
Neuropathological data are unavailable. However, Aβ42 levels in cerebrospinal fluid were reduced in one mutation carrier, and phospho-tau levels were elevated in another (Itzcovich et al., 2019). Moreover, PiB-PET revealed amyloid deposition in frontal, parietal, precuneus/posterior cingulate, lateral temporal, and striatal regions in one mutation carrier. In addition, PET-FDG demonstrated mild bilateral hypometabolism in the parietal lobe, precuneus, anterior cingulate, dorsal frontal lobe, and lateral temporal lobe with left predominance in one patient (Itzcovich et al., 2019), and bilateral hypometabolism in parietal and temporal cortices in another (Giau et al., 2019).

Biological Effect
In silico analyses yielded variable results, but suggested deleterious effects (Itzcovich et al., 2019; Giau et al., 2019). Itzcovich and colleagues reported the mutation to be possibly damaging (PolyPhen2) or damaging (SIFT), while Giau et al.’s predictions included damaging (PolyPhen2), tolerated (SIFT), and neutral (Provean). Moreover, Giau et al. reported the mutation is predicted to result in major helical torsion in the conserved HL-I loop. They also noted that other threonine to isoleucine substitutions in this loop are associated with aggressive AD phenotypes. Lastly, the CADD-PHRED score reported by Itzcovich et al. was 24, suggesting it is in the top one percent of most deleterious variants in the genome.

Following guidelines from the American College of Medical Genetics and Genomics (Richards et al., 2015), Itzcovich and colleagues classified the variant  as “likely pathogenic."

Last Updated: 03 Jul 2019

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References

Paper Citations

  1. . A novel mutation in PSEN1 (p.T119I) in an Argentine family with early- and late-onset Alzheimer's disease. Neurobiol Aging. 2019 May 9; PubMed.
  2. . Genetic analyses of early-onset Alzheimer's disease using next generation sequencing. Sci Rep. 2019 Jun 10;9(1):8368. PubMed.
  3. . Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405-24. Epub 2015 Mar 5 PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . A novel mutation in PSEN1 (p.T119I) in an Argentine family with early- and late-onset Alzheimer's disease. Neurobiol Aging. 2019 May 9; PubMed.
  2. . Genetic analyses of early-onset Alzheimer's disease using next generation sequencing. Sci Rep. 2019 Jun 10;9(1):8368. PubMed.

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