Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PM1, PM2
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73640281_73640284 ACCC>TCTA
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Deletion-Insertion
Expected RNA Consequence: Deletion-Insertion
Expected Protein Consequence: Deletion-Insertion
Codon Change: ACC CCA to TCT ACA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 5

Findings

This mutation was identified in a Spanish family with nine members affected by AD, spanning five generations (Blanco et al., 2019). The proband was a 37-year-old man admitted to a psychiatric ward with multiple cognitive impairments, including disorientation, visual hallucinations, speech alterations, severe memory loss, as well as visuospatial and praxis deficits.  He also had a history of thalassemia minor and migraine headaches, and presented with mild bradykinesia, hyperreflexia, and a tendency to swerve left when walking. His unaffected sister reported he had been suffering progressive cognitive decline during the last two years.

Descriptions provided by family members of the other eight affected individuals, together with clinical records from four of these patients, revealed they all developed similar symptoms during their 30s. In addition, two of the clinical records reported spastic paraparesis, and the other two noted ataxic gait and myoclonus.  The mutation was found in the proband and an affected uncle. It was absent from the gnomAD variant database (gnomAD v2.1.1, August 2021).

Neuropathology
Brain biopsies from two patients showed neurofibrillary tangles and neuritic plaques consistent with AD. Also, levels of AD biomarkers in the proband's cerebrospinal fluid, including Aβ42, total tau, and phosphorylated tau, were typical of AD.

An MRI scan of the proband’s brain revealed white matter lesions and diffuse cortical atrophy, while SPECT showed frontoparietal hypoperfusion, mainly of the right hemisphere. A CT scan of another affected family member revealed severe cortical and subcortical atrophy.

Biological Effect
This mutation substitutes the T116 codon, ACC, and the first C of the P117 codon for TCTA resulting in the replacement of T116 with a serine and P117 with a threonine. Both T116 and P117 have been identified as key for PSEN1's γ-processivity, the carboxypeptidase activity that trims Aβ intermediates to form shorter, secreted species (Liu et al., 2021).

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) yielded conflicting results (Blanco et al., 2019, Xiao et al., 2021). PredictSNP categorized the T116S substitution as neutral, and P117T as pathogenic (Blanco et al., 2019).

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: it was found in a single affected family without clear evidence of cosegregation or a functional effect, and it 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. Blanco JA, Alonso A, Blanco J, Rojo E, Tellería JJ, Torres MA, Uribe F. Novel presenilin 1 mutation (p.Thr-Pro116-117Ser-Thr) in a Spanish family with early-onset Alzheimer's disease. Neurobiol Aging. 2019 May 20; 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.

External Citations

1. gnomAD v2.1.1

Further Reading

No Available Further Reading