Mutations

PSEN1 T147I

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Genome Build: 105
Position: Chr14:73640375 C>T
dbSNP ID: rs63750907
Coding/Non-Coding: Coding
Genomic Region: Exon 5
Mutation Type: Point, Missense
Codon Change: ACT to ATT

Findings

This mutation was detected in a French kindred (Alz 047), reported to have four affected individuals over three generations. The symptoms were described as being fairly typical of Alzheimer's disease, with onset ranging from age 37 to 46. Segregation with disease was confirmed (Campion et al., 1999).

This mutation was later found in four members of a large American kindred affected by very early onset dementia (Denvir et al., 2015). The reported pedigree shows 19 affected members over five generations in a pattern indicative of autosomal-dominant inheritance. All affected members developed cognitive decline in their mid- to late 20s. In addition to cognitive impairment, the four known mutation carriers, a mother-daughter dyad and two cousins of the daughter, exhibited features atypical of AD, including limb spasticity and early loss of expressive speech. In brief, the daughter first experienced cognitive decline at age 27. She developed expressive aphasia, dysphagia, and motor impairment due to prominent myoclonic jerks and increased muscle tone. At the time of the report, her mother was 57 years old and had advanced dementia. She had been admitted to a nursing home at age 38. Little is known about her clinical history other than that she had seizures by age 35 and evidence of cognitive impairment prior to that. Both the mother and daughter had APOE genotypes of ε3/ε4. Not much is known about the two affected cousins: One died at age 36 and the other was alive at age 37.

Neuropathology

Unknown.

Biological Effect

Unknown. Predicted to be probably damaging by in silico analysis using PolyPhen-2 (Denvir et al., 2015).

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References

Paper Citations

  1. . Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am J Hum Genet. 1999 Sep;65(3):664-70. PubMed.
  2. . Identification of the PS1 Thr147Ile Variant in a Family with Very Early Onset Dementia and Expressive Aphasia. J Alzheimers Dis. 2015 May 30;46(2):483-90. PubMed.

Further Reading

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Primary Papers

  1. . Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am J Hum Genet. 1999 Sep;65(3):664-70. PubMed.

Other mutations at this position

Alzpedia