Mutations

PSEN1 T354I

Overview

Pathogenicity: Alzheimer's Disease : Unclear Pathogenicity
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73678582 C>T
dbSNP ID: rs63751164
Coding/Non-Coding: Coding
Genomic Region: Exon 10
Mutation Type: Point, Missense
Codon Change: ACA to ATA

Findings

This variant was first reported in one person with Alzheimer’s disease in a large genetic screen. Clinical details and family history information were not reported (Rogaeva et al., 2001).

This variant was subsequently identified in a 46-year-old man with a five-year history of cognitive decline (Lee et al., 2006). He had a family history consistent with AD: Two of his father’s siblings developed memory impairment in their early 40s, and both had died approximately five years later. His father had died of an accident at age 32, so whether he would have developed dementia is unknown.

This case is unusual because in addition to carrying the T354I variant, the proband carried a second presenilin-1 variant, the A431E (Jalisco) mutation. His father’s family had ancestral ties to the Mexican state of Jalisco. The Jalisco mutation is pathogenic and alone could account for the patient’s early onset AD. The significance of the T354I mutation is unknown; it may be a rare benign polymorphism. The proband’s 81-year-old grandmother carried the T354I variant, but not the Jalisco mutation. She had cognitive symptoms, including deficits in recent memory and orientation, and was considered to have moderate dementia. Her APOE genotype was 3/4.

Neuropathology

Unknown. Brain imaging showed severe generalized atrophy (Lee et al., 2006).

Biological Effect

Unknown.

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References

Mutations Citations

  1. PSEN1 A431E (Jalisco)

Paper Citations

  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. . The Thr354Ile substitution in PSEN1:: disease-causing mutation or polymorphism?. Neurology. 2006 Jun 27;66(12):1955-6. PubMed.

Further Reading

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

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. . The Thr354Ile substitution in PSEN1:: disease-causing mutation or polymorphism?. Neurology. 2006 Jun 27;66(12):1955-6. PubMed.

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