Mutations

PSEN1 H163Y

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Genomic Mutation Name (MET1): g.38784C>T
Genomic Mutation Name (NT1): g.55389C>T
dbSNP ID: rs63749885
Coding/Non-Coding: Coding
Genomic Region: Exon 5
Mutation Type: Point, Missense
Codon Change: CAT to TAT

Findings

This mutation has been identified in a Swedish family known as "Swed2". Originally eight affected individuals were reported over three generations, with memory difficulties beginning at 47 years on average (Clark et al., 1995). A follow-up study described the clinical details of this family in greater depth and published an extended pedigree with 101 individuals over six generations, 18 of whom were affected by dementia. Clinical data were available for 16 of the 18 affected family members and revealed that disease onset in this family was particularly variable, ranging from 44-65 years (mean: 54 years, n=16). Variability was also noted in disease duration (5-23 years) and age at death (55-83 years). A commonality among affected individuals was insidious memory loss as the primary presenting feature. Psychiatric problems were also common, and myoclonic jerks and epileptic seizures occurred later in 10 of 16 patients. The mode of inheritance was consistent with autosomal dominant inheritance in this family; however, one obligate carrier died at age 67 unaffected by dementia. Whether this was due to incomplete penetrance or a very late onset is unknown (Axelman et al., 1998).

Neuropathology

The neuropathology associated with this mutation in unknown. Cerebral glucose metabolism appears to be affected early in the disease process, as FDG-PET imaging showed that young, pre-symptomatic H163Y carriers had decreased glucose metabolism, especially in the thalamus, many years prior to the development of clinical symptoms of AD (Schöll et al., 2011).

Biological Effect

Increased Aβ42/Aβtotal ratio when expressed in COS-1 cells cotransfected with APP695 (Murayama et al., 1999).

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References

Paper Citations

  1. The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families. Alzheimer's Disease Collaborative Group. Nat Genet. 1995 Oct;11(2):207-9. PubMed.
  2. . Wide range of disease onset in a family with Alzheimer disease and a His163Tyr mutation in the presenilin-1 gene. Arch Neurol. 1998 May;55(5):698-702. PubMed.
  3. . Glucose metabolism and PIB binding in carriers of a His163Tyr presenilin 1 mutation. Neurobiol Aging. 2011 Aug;32(8):1388-99. PubMed.
  4. . Enhancement of amyloid beta 42 secretion by 28 different presenilin 1 mutations of familial Alzheimer's disease. Neurosci Lett. 1999 Apr 9;265(1):61-3. PubMed.

Further Reading

Learn More

Alzheimer Disease & Frontotemporal Dementia Mutation Database