Overview

Pathogenicity: Frontotemporal Dementia : Pathogenic
Clinical Phenotype: Frontotemporal Dementia
Position: (GRCh38/hg38):Chr17:46024034 C>T
Position: (GRCh37/hg19):Chr17:44101400 C>T
dbSNP ID: rs1295855402
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CCA to TCA
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 13

Findings

The P397S variant initially was described in eight Spanish patients diagnosed with behavioral variant frontotemporal dementia (bvFTD) (Borrego-Écija et al., 2019). The patients were from five separate families, each of whom included multiple relatives who suffered from FTD, with pedigrees supporting an autosomal-dominant pattern of inheritance. Although apparently unrelated, the families could be traced to a common region in southeast Spain, suggesting a possible founder effect originating in this area.

This variant also has been found in three Colombian FTD families (personal communication, Francisco Lopera, Juliana Acosta-Uribe, David Aguillon, Nick Cochran, Kenneth S. Kosik; see Alzforum news story).

The description below refers to the Spanish families, as reported by Sánchez-Valle and colleagues (Borrego-Écija et al.., 2019).

All carriers of this variant exhibited behavioral problems and language impairments. Three of the eight also developed mild rigid-akinetic parkinsonism. The average age of onset of symptoms of the carriers and their affected relatives was approximately 61 years, with an average disease duration of 14 years.

CSF biomarkers were measured in three carriers. Total tau and phospho-tau were elevated in all three patients, and one patient additionally showed decreased levels of Aβ42. This latter subject was initially diagnosed with Alzheimer’s disease based on clinical and biomarker findings, but the diagnosis was subsequently revised to bvFTD as his presenting symptoms—memory loss and behavioral disinhibition—progressed to include severe apathy, loss of empathy, hyperorality, executive dysfunction, and mild rigid-akinetic parkinsonism.

MRI revealed bilateral temporal atrophy with relative sparing of the frontal lobes in all carriers.

Thus far, the variant appears to segregate with disease, although genetic information from additional family members is needed to strengthen this inference: The variant is present in all genotyped patients, and absent in the single unaffected individual who was genotyped, a 68-year-old sibling of one of the probands. The variant was not found in the gnomAD database.

The P397S variant is classified as likely pathogenic according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology guidelines and as definitely pathogenic by the criteria of Guerreiro and colleagues (Guerreiro et al., 2008).

Neuropathology

Neuropathological data are not yet available, although all carriers exhibited bilateral temporal lobe atrophy on MRI.

Biological Effect

The biological effect of this variant is not yet known. In silico predictions yielded a range of results: The variant was predicted to be pathogenic by SIFT, probably damaging by Polyphen-2, but likely benign by CADD and REVEL, tolerated by MetaLR, and without a functional consequence by Mutation Assessor (Borrego-Écija et al., 2019). The proline-to-serine change at amino acid 397 should prevent phosphorylation of the adjacent serine 396 by proline-directed kinases, including GSK-3β. Notably, phosphorylated serine 396 is one of the epitopes recognized by monoclonal antibody PHF-1 (Otvos et al., 1994), and phosphorylation at this site was required for the expression of long-term depression at Schaffer collateral-CA1 hippocampal synapses (Regan et al., 2015).

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References

News Citations

1. Geneticists Seek Out Rare Contributors to Alzheimer’s 15 Aug 2019

Paper Citations

1. Borrego-Écija S, Antonell A, Puig-Butillé JA, Pericot I, Prat-Bravo C, Abellan-Vidal MT, Mallada J, Olives J, Falgàs N, Oliva R, Lladó A, Sánchez-Valle R. Novel P397S MAPT variant associated with late onset and slow progressive frontotemporal dementia. Ann Clin Transl Neurol. 2019 Aug;6(8):1559-1565. Epub 2019 Jul 17 PubMed.
2. Guerreiro RJ, Baquero M, Blesa R, Boada M, Brás JM, Bullido MJ, Calado A, Crook R, Ferreira C, Frank A, Gómez-Isla T, Hernández I, Lleó A, Machado A, Martínez-Lage P, Masdeu J, Molina-Porcel L, Molinuevo JL, Pastor P, Pérez-Tur J, Relvas R, Oliveira CR, Ribeiro MH, Rogaeva E, Sa A, Samaranch L, Sánchez-Valle R, Santana I, Tàrraga L, Valdivieso F, Singleton A, Hardy J, Clarimón J. Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP. Neurobiol Aging. 2010 May;31(5):725-31. Epub 2008 Jul 30 PubMed.
3. Otvos L Jr, Feiner L, Lang E, Szendrei GI, Goedert M, Lee VM. Monoclonal antibody PHF-1 recognizes tau protein phosphorylated at serine residues 396 and 404. J Neurosci Res. 1994 Dec 15;39(6):669-73. PubMed.
4. Regan P, Piers T, Yi JH, Kim DH, Huh S, Park SJ, Ryu JH, Whitcomb DJ, Cho K. Tau Phosphorylation at Serine 396 Residue Is Required for Hippocampal LTD. J Neurosci. 2015 Mar 25;35(12):4804-12. PubMed.

Further Reading