Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM5, PP2, PP3, BS2
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73186859 C>T
Position: (GRCh37/hg19):Chr14:73653567 C>T
dbSNP ID: rs63749885
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CAT to TAT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 5

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 age 47 on average (Clark et al., 1995). Formal linkage analysis yielded an LOD score greater than 3. 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 to 65 years (mean: 54 years, n=16). Variability was also noted in disease duration (five to 23 years) and age at death (55 to 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 (Axelman et al., 1998). Incomplete penetrance has been described in an H163Y carrier who, in parallel with an affected brother, was followed prospectively for 22 years. The affected brother experienced symptom onset at 54 and died at 64 with typical AD neuropathology. His cognition deteriorated across ten years, and he experienced AD-associated changes in magnetic resonance imaging (MRI), amyloid positron emission tomography (PiB-PET), and cerebrospinal fluid (CSF) levels of amyloid-β42, total tau, and phosphorylated tau. In contrast, the unaffected sibling, remained symptom-free at age 65, had normal levels of all three CSF biomarkers at 54 (three years past the mean age of symptom onset in his family), and a normal PiB-PET scan at 60 (nine years past the mean onset age) (Thordardottir et al., 2018).

This variant was absent from the gnomAD variant database (gnomAD v2.1.1, June 2021).

Neuropathology

The neuropathology associated with this mutation is typical of AD, as described for one case. Cerebral glucose metabolism may be affected early, as FDG-PET imaging showed that young, presymptomatic 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). Three years after symptom onset, PiB-PET in one individual revealed widespread Aβ in the brain, except the thalamus, caudate nucleus, and hippocampus. MRI revealed shrunken hippocampi.

Biological Effect

Average CSF Aβ42 and Aβ38 levels were decreased in eight members of a family carrying this mutation (Thordardottir et al., 2017). In addition, the ratio of Aβ42/Aβ total was increased in COS-1 cells co-transfected with H163Y presenilin and APP695 (Murayama et al., 1999). Consistent with this observation, an in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate revealed H163Y generates more Aβ42 than the wild-type protein, resulting in elevated  Aβ42/Aβ40 (Sun et al., 2017).

Although some in silico algorithms to predict the effects of this variant on protein function yielded conflicting results (Xiao et al., 2021), the CADD-PHRED tool, which integrates diverse information, gave it a high deleteriousness score above 20 (CADD v.1.6, Sep 2021).

Pathogenicity

Alzheimer's Disease : Pathogenic*

*This variant may have reduced penetrance, a condition outside the scope of the ACMG-AMP guidelines.

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

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References

Paper Citations

1. Alzheimer's Disease Collaborative Group. The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families. Nat Genet. 1995 Oct;11(2):219-22. PubMed.
2. Axelman K, Basun H, Lannfelt L. 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. Thordardottir S, Rodriguez-Vieitez E, Almkvist O, Ferreira D, Saint-Aubert L, Kinhult-Ståhlbom A, Thonberg H, Schöll M, Westman E, Wall A, Eriksdotter M, Zetterberg H, Blennow K, Nordberg A, Graff C. Reduced penetrance of the PSEN1 H163Y autosomal dominant Alzheimer mutation: a 22-year follow-up study. Alzheimers Res Ther. 2018 May 10;10(1):45. PubMed.
4. Schöll M, Almkvist O, Axelman K, Stefanova E, Wall A, Westman E, Långström B, Lannfelt L, Graff C, Nordberg A. Glucose metabolism and PIB binding in carriers of a His163Tyr presenilin 1 mutation. Neurobiol Aging. 2011 Aug;32(8):1388-99. PubMed.
5. Thordardottir S, Kinhult Ståhlbom A, Almkvist O, Thonberg H, Eriksdotter M, Zetterberg H, Blennow K, Graff C. The effects of different familial Alzheimer's disease mutations on APP processing in vivo. Alzheimers Res Ther. 2017 Feb 16;9(1):9. PubMed.
6. Murayama O, Tomita T, Nihonmatsu N, Murayama M, Sun X, Honda T, Iwatsubo T, Takashima A. 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.
7. Sun L, Zhou R, Yang G, Shi Y. Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase. Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E476-E485. Epub 2016 Dec 5 PubMed.
8. Xiao X, Liu H, Liu X, Zhang W, Zhang S, Jiao B. APP, PSEN1, and PSEN2 Variants in Alzheimer's Disease: Systematic Re-evaluation According to ACMG Guidelines. Front Aging Neurosci. 2021;13:695808. Epub 2021 Jun 18 PubMed.

External Citations

1. gnomAD v2.1.1
2. CADD v.1.6

Further Reading