Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM5, PP2
Clinical Phenotype: Alzheimer's Disease
dbSNP ID: NA
Coding/Non-Coding: Coding
Expected Protein Consequence: Missense
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 5

Findings

This mutation was reported in a study describing the clinical and genetic attributes of 54 Alzheimer's disease cases linked to mutations in PSEN1. The one reported individual with a T116R mutation experienced symptom onset age 35 and died at the age of 43. His APOE genotype was E3/E4. Neither the nucleotide sequence change nor additional clinical details were reported, and the proband's family history is unknown (Mann et al., 2001).

Neuropathology

Unknown.

Biological Effect

This mutant severely reduces γ-processivity (Liu et al., 2021). Analysis of secreted Aβs in the conditioned media of human embryonic kidney cells lacking endogenous PSENs and expressing this mutant along with wildtype APP, revealed increased Aβ42/40 ratio and decreased Aβ37/40, Aβ37/42, and Aβ38/42 ratios. More specifcally, compared with wildtype PSEN1, this mutant increased the Aβ42/40 ratio 684 percent, decreased Aβ37/42 and Aβ38/42 by 90% and 94%, respectively; and increased Aβ43 eightfold. It increased Aβ42 and 43 production at the expense of Aβ37, 38 and 40, and led to 32 percent less total Aβ secretion. Interestingly, the authors reported that Aβ42/40, Aβ38/42, and particularly Aβ37/42, ratios each correlated with reported ages of onset of clinical impairment across 16 PSEN1 mutations. 

In silico algorithms to predict the effects of this variant on protein function (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) yielded conflicting results (Xiao et al., 2021). The variant's CADD score was unavailable.

Pathogenicity

Alzheimer's Disease : Not Classified*

*This variant fulfilled some ACMG-AMP criteria, but it was not classified by Alzforum, because data for either a pathogenic or benign classification are lacking: only one affected carrier has been reported without co-segregation data, and the variant is absent—or very rare—in the gnomAD database.

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. Mann DM, Pickering-Brown SM, Takeuchi A, Iwatsubo T, . Amyloid angiopathy and variability in amyloid beta deposition is determined by mutation position in presenilin-1-linked Alzheimer's disease. Am J Pathol. 2001 Jun;158(6):2165-75. PubMed.
2. Liu L, Lauro BM, Wolfe MS, Selkoe DJ. Hydrophilic loop 1 of Presenilin-1 and the APP GxxxG transmembrane motif regulate γ-secretase function in generating Alzheimer-causing Aβ peptides. J Biol Chem. 2021;296:100393. Epub 2021 Feb 8 PubMed.
3. 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.

Further Reading