Overview

Pathogenicity: Alzheimer's Disease : Not Classified, Spastic Paraparesis, Parkinsonism
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73219134 G>A
Position: (GRCh37/hg19):Chr14:73685842 G>A
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GGT to AGT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 12

Findings

This mutation has been identified in individuals with heterogenous clinical phenotypes. It was originally reported in a Japanese woman who initially presented with cognitive impairment, muscle weakness in the hands, and forgetfulness in her mid-20s (Miki et al., 2019). Over the next few years, her motor and cognitive symptoms worsened and she was suspected of having AD with parkinsonism, including spastic paraperesis. Her decline was slow, however, with a disease duration of 29 years. She had no other mutations in either APP or PSEN2. Her APOE genotype was APOE3/E4. Her final neurological diagnosis was unclassifiable dementia. The patient’s brother, mother, uncle, and maternal grandfather suffered from dementia and/or gait disturbance, and all died in their late ‘40s. However, no genetic data are available for these relatives.

The variant was also found in a Chinese family with early onset parkinsonism and cognitive impairment, including memory loss and visuo-spatial dysfunction (Jiang et al., 2022). The proband, a 42-year-old woman whose symptoms began at age 41, had a strong family history of these conditions. Ten affected individuals, spanning three generations,  developed rapidly progressing parkinsonism and cognitive disturbances in their third or fourth decades of life. In addition, one of the proband's brothers and two of her cousins suffered from memory loss and other cognitive impairments in their late 30s, but had no motor symptoms at ages 39 and 40 years old.

Whole-exome sequencing of the proband's DNA revealed the G417S mutation. The variant was also identified in the affected brother and cousins, but not in 13 unaffected family members. Three of the non-carriers were 65 or older, well past the age of disease onset, indicating the mutation co-segregated with disease.    

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

Neuropathology

Autopsy of the Japanese woman's brain revealed cotton- wool plaques throughout the cortex, abundant Aβ deposits in the cerebellum and spinal gray matter (Miki et al., 2019). Also, cerebral amyloid angiopathy, extensive neuronal loss, astrocytic and microglial markers, and extensive distribution of neocortical Lewy bodies were observed. Moreover, TDP-43 inclusions in the limbic region and temporal cortex were reported.

Brain MRI of this patient at 40 years revealed diffuse cerebral atrophy, and at 44 years, single-photon emission- computed tomography (SPECT) showed hypoperfusion in the posterior part of the cingulate gyrus, precuneus, and parieto-occipital cortices (Miki et al., 2019). 

In contrast, brain MRI of the four affected Chinese carriers revealed white matter hyperintensities in periventricular areas and deep white matter of the frontal, parietal and occipital lobes, without typical medial temporal lobe atrophy or diffuse cerebral atrophy (Jiang et al., 2022). In addition, multiple microbleeds, mostly in posterior areas, were observed in these patients, as well as enlarged perivascular spaces in the basal ganglia and centrum semiovale.

Biological Effect

An assay using neuroblastoma N2a cells expressing either wildtype PSEN1 or G417S revealed the mutant protein increased levels of Aβ42 and the Aβ42/Aβ40 ratio (Miki et al., 2019).

Of note, the nucleotide substitution of this variant is near a known acceptor and a potential donor splice sites which could result in abnormal splicing (Giau et al., 2018). However, RT-PCR and cDNA sequencing failed to detect any splicing abnormalities (Jiang et al., 2022).

Modeling of the mutant protein's 3D structure using Missense3D suggested contact with the lipid membrane may be disrupted by the substitution of glycine with serine, a larger amino acid (Jiang et al., 2022). Several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) predicted this variant is damaging (Xiao et al., 2021). 

Pathogenicity

Alzheimer's Disease : Not Classified*

*This variant fulfilled several ACMG-AMP criteria, but it was not classified by Alzforum because the reported carriers had heterogenous phenotypes and the variant's relationship to AD was unclear.

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. Miki T, Yokota O, Haraguchi T, Ikeuchi T, Zhu B, Takenoshita S, Terada S, Yamada N. Young adult-onset, very slowly progressive cognitive decline with spastic paraparesis in Alzheimer's disease with cotton wool plaques due to a novel presenilin1 G417S mutation. Acta Neuropathol Commun. 2019 Feb 12;7(1):19. PubMed.
2. Jiang L, Qin Y, Zhao YW, Zeng Q, Pan HX, Liu ZH, Sun QY, Xu Q, Tan JQ, Yan XX, Li JC, Tang BS, Guo JF. PSEN1 G417S mutation in a Chinese pedigree causing early-onset parkinsonism with cognitive impairment. Neurobiol Aging. 2022 Jul;115:70-76. Epub 2022 Apr 11 PubMed.
3. Giau VV, Wang MJ, Bagyinszky E, Youn YC, An SS, Kim S. Novel PSEN1 p.Gly417Ala mutation in a Korean patient with early-onset Alzheimer's disease with parkinsonism. Neurobiol Aging. 2018 Dec;72:188.e13-188.e17. Epub 2018 Aug 9 PubMed.
4. 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

Further Reading

No Available Further Reading