Mutations

PSEN1 G206V

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73659420 G>T
dbSNP ID: rs63750082
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GGT to GTT
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This mutation has been reported in the proband of a family with multigenerational, early onset Alzheimer’s disease. The reported pedigree shows four affected individuals over three generations. The proband, EN, developed disorientation at age 30 with insidious onset of memory impairment. He died at 39 with a diagnosis of AD. His mother died of autopsy-confirmed AD at age 42, with onset in her early 30s. Her first symptoms were confusion, handwriting changes, word-finding problems, short-term memory loss, and anger. She later developed severe loss of language and motor skills, disorientation, seizures, and blindness. The proband’s maternal grandfather died of an unspecified dementia in his early 40s. The G206V mutation was hypothesized to be pathogenic, but confirmation was not possible in this family as the other affected family members were deceased (Goldman et al., 2002).

The mutation was also found in a Chinese AD patient who experienced progressive memory loss combined with irritability and anxiety, starting at age 30 (Li et al., 2019). No additional members of his family had AD and analyses of DNA microsatellite markers suggested the mutation occurred de novo. The mutation was absent from 200 Chinese healthy controls and two genetic variant databases (ExAC and 1000 Genomes).

Neuropathology

Unknown. In one case, MRI revealed mild atrophy of the brain with normal temporal lobes (Goldman et al., 2002), but in another, it showed temporal and hippocampal atrophy (Li et al., 2019).  

Biological Effect

Unknown. A cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment suggests mutations in this residue could alter the protein's local conformation and affect the positioning of residues that directly contribute to substrate binding (Zhou et al., 2019; Jan 2019 news).

Last Updated: 26 Aug 2019

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References

News Citations

  1. CryoEM γ-Secretase Structures Nail APP, Notch Binding

Paper Citations

  1. . Very early-onset familial Alzheimer's disease: a novel presenilin 1 mutation. Int J Geriatr Psychiatry. 2002 Jul;17(7):649-51. PubMed.
  2. . Two Novel Mutations and a de novo Mutation in PSEN1 in Early-onset Alzheimer's Disease. Aging Dis. 2019 Aug;10(4):908-914. PubMed.
  3. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Very early-onset familial Alzheimer's disease: a novel presenilin 1 mutation. Int J Geriatr Psychiatry. 2002 Jul;17(7):649-51. PubMed.

Other mutations at this position

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