Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS2, PS3, PS4, PM1, PM2, PM5, PP2
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73186902 T>C
Position: (GRCh37/hg19):Chr14:73653610 T>C
dbSNP ID: rs63749806
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: TTT to TCT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 6

Findings

This mutation was first found in a screen for variants in the open reading frame of the PSEN1 gene in participants from the U.S., Germany, and Canada who had been referred for AD diagnostic testing (Rogaeva et al., 2001).

Subsequently, the mutation was reported in two members of a German family spanning seven generations with eight of 21 members affected by early onset AD (Hausner et al., 2014).  Only two affected individuals underwent genetic analysis and were shown to be carriers. Thus, co-segregation was not definitively established. The expression of disease in the family suggested autosomal dominant transmission. Onset of dementia was between 29 and 31 years of age, with death before age 40. The dementia progressed rapidly and neurological features, including myoclonia, epileptic seizures, and pyramidal signs, were reported. There was little variability between individuals’ disease progression.

The mutation was also found in two Chinese individuals. A screen involving whole-exome sequencing of 15 unrelated Chinese patients with familial AD identified a man who suffered from memory loss when he was 30 years old, and developed involuntary movements, cerebellar ataxia, and difficulties speaking and swallowing (Jiang et al., 2019). Three members of his family, spanning two generations, were affected by dementia, two of whom died in their 30s. The other Chinese carrier was a man who developed memory impairment at age 27 and later dyscalculia, disorientation, aphasia, agraphia, and psychiatric symptoms (Chen et al., 2022). Of note, the parents of this patient did not carry the mutation, indicating the mutation arose de novo.

This variant was absent from the gnomAD variant database (V2.1.1, Jan 2022).

Neuropathology
Amyloid PET of one carrier revealed amyloid pathology in frontal, parietal, temporal, and posterior cingulate cortices, while tau PET indicated tau pathology in whole cerebral gray matter, basal ganglia, thalamus, pons, midbrain, and cerebellum (Chen et al., 2022). 

Also, in three affected mutation carriers, MRI revealed widespread brain atrophy which, in two cases, was particularly pronounced in cortical temporal regions and hippocampus (Jiang et al., 2019; Chen et al., 2022). In one of these cases, frontal regions and the cerebellum were markedly affected as well (Jiang et al., 2019). Moreover, FDG-PET scans of two affected mutation carriers showed a progressive drop in parietal and temporoparietal glucose metabolism (Hausner et al., 2014) and, in another case, widespread cortical hypometabolism (Chen et al., 2022). Levels of Aβ42 were decreased, while total tau was increased in the CSF of two of these patients (Hausner et al., 2014; Chen et al., 2022) and, in one case, pshosphorylated tau at threonine 181 was within the upper limit of the normal range (Chen et al., 2022).

Autopsies of two members of the German family who were not tested genetically revealed neuropathology typical of AD, with cortical brain atrophy, abundant senile plaques, and neurofibrillary tangles (Hausner et al., 2014).

Biological Effect

In conditioned media of human embryonic kidney cells lacking endogenous PSEN1 and PSEN2 and expressing this variant, the Aβ42/Aβ40 ratio was elevated compared with that of control cells, and the Aβ37/Aβ42 ratio was decreased, suggesting a damaging effect (Liu et al., 2022, Apr 2022 news). Of note, the Aβ37/Aβ42 ratio outperformed Aβ42/Aβ40 at distinguishing control versus AD samples.

According to  cryo-electron microscopy studies of the atomic structure of γ-secretase bound to Notch or APP fragments indicate F177 directly interacts with residues from Notch, but not APP (Zhou et al., 2019; Yang et al., 2019; Jan 2019 news). Two other mutations at this site, F177L and F177V, have been reported in individuals with a strong family history of AD.

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 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

News Citations

1. Ratio of Short to Long Aβ Peptides: Better Handle on Alzheimer's than Aβ42/40? 20 Apr 2022
2. CryoEM γ-Secretase Structures Nail APP, Notch Binding 11 Jan 2019

Mutations Citations

1. PSEN1 F177L
2. PSEN1 F177V

Paper Citations

1. Rogaeva EA, Fafel KC, Song YQ, Medeiros H, Sato C, Liang Y, Richard E, Rogaev EI, Frommelt P, Sadovnick AD, Meschino W, Rockwood K, Boss MA, Mayeux R, St George-Hyslop P. 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. Hausner L, Tschäpe JA, Schmitt HP, Hentschel F, Hartmann T, Frölich L. Clinical characterization of a presenilin 1 mutation (F177S) in a family with very early-onset Alzheimer's disease in the third decade of life. Alzheimers Dement. 2013 Jul 11; PubMed.
3. Jiang B, Zhou J, Li HL, Chen YG, Cheng HR, Ye LQ, Liu DS, Chen DF, Tao QQ, Wu ZY. Mutation screening in Chinese patients with familial Alzheimer's disease by whole-exome sequencing. Neurobiol Aging. 2019 Apr;76:215.e15-215.e21. Epub 2018 Dec 6 PubMed.
4. Chen KL, Li PX, Sun YM, Chen SF, Zuo CT, Wang J, Dong Q, Cui M, Yu JT. Very Early-Onset Alzheimer's Disease in the Third Decade of Life with de novo PSEN1 Mutations. J Alzheimers Dis. 2022;85(1):65-71. PubMed.
5. Liu L, Lauro BM, He A, Lee H, Bhattarai S, Wolfe MS, Bennett DA, Karch CM, Young-Pearse T, Dominantly Inherited Alzheimer Network (DIAN), Selkoe DJ. Identification of the Aβ37/42 peptide ratio in CSF as an improved Aβ biomarker for Alzheimer's disease. Alzheimers Dement. 2022 Mar 12; PubMed.
6. Zhou R, Yang G, Guo X, Zhou Q, Lei J, Shi Y. Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
7. Yang G, Zhou R, Zhou Q, Guo X, Yan C, Ke M, Lei J, Shi Y. Structural basis of Notch recognition by human γ-secretase. Nature. 2019 Jan;565(7738):192-197. Epub 2018 Dec 31 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. CADD v.1.6

Further Reading

No Available Further Reading