Overview

Pathogenicity: Frontotemporal Dementia : Pathogenic, Alzheimer's Disease : Not Classified
Clinical Phenotype: Frontotemporal Dementia, nfvPPA, bvFTD
Position: (GRCh38/hg38):Chr17:46010379 A>G
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Splicing Alteration; Substitution
Expected Protein Consequence: Isoform Shift; Missense
Codon Change: AAA to GAA
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 10

Findings

The K298E variant was first reported in a a patient from the UK with frontotemporal dementia (FTD) and parkinsonism (Iovino et al., 2014). She was a 67-year-old woman who presented with gait difficulties and non-fluent aphasia that had been worsening for 2 years. Decades earlier, at the age of 48, she had developed a minor tremor in her right hand, which worsened and became bilateral by age 65. From age 65 to 67 her condition deteriorated rapidly. She was ultimately unable to stand or sit unaided, had severe cognitive impairment, and paucity of speech. In addition to tremor, she had increased limb tone, spasticity, and altered reflexes. She died at the age of 68. The proband’s father had Alzheimer’s disease (diagnosed in his 60s) and died at the age of 67, but no other family members were reported to have dementia. 

Subsequently, an Italian family including four of 11 siblings who had FTD and carried the K298E mutation was reported. The affected carriers showed a variable clinical presentation and progression, although all had a relatively early onset of disease (Pozzi et al., 2024). Of note, based on Alzforum’s guidelines, co-segregation of the variant with disease could not be established given that no unaffected non-carriers were reported.

The proband in this family exhibited behavioral issues starting at age 57, and was clinically evaluated at age 60, at which point he had advanced dementia. He was diagnosed with the behavioral variant of FTD (bvFTD). His behavioral issues included social withdrawal, lack of empathy, and claustrophobia. 

The second sibling was also diagnosed with bvFTD with a similar age of onset. His initial symptoms included impulsivity, disinhibition, and food cravings, alongside speech issues. He had mild deficits in short-term memory  and cognitive function. As his condition progressed, he developed motor symptoms, including right-sided limb weakness, gait instability, and frequent falls, and ultimately became mute. He also displayed increased agitation and hyperphagia.

The third sibling, a 52-year-old woman, had a background of depression and apathy. She was later diagnosed with right temporal variant FTD (rtvFTD) based on neuroimaging. She displayed early memory lapses in everyday activities. While her speech remained fluent, it was occasionally marred by anomia, and she did not seem to be fully aware of her cognitive challenges. Half a year after her initial examination, she developed progressive left leg weakness, and neurologic examination revealed additional neuromuscular defects, including diffuse paratonic rigidity and distal dyskinesia predominantly affecting her left lower limb. Despite these symptoms, muscle ultrasound did not show any fasciculations, and her motor nerve conduction studies and EMG were normal.

The fourth sibling, a 62-year-old woman, experienced two episodes of generalized seizures prior to examination. Additional seizures occurred in the following months, along with progressive cognitive impairment. Clinical and psychometric testing led to a bvFTD diagnosis.

The father of the family was diagnosed with dementia not otherwise specified at age 67, and one deceased brother also had dementia, although neither underwent mutational analysis. The deceased brother was presumed to have had FTD. 

In an international, retrospective cohort study, two carriers from one family were identified in the Frontotemporal Dementia Prevention Initiative and the published literature, including one with Alzheimer’s disease and one with bvFTD (Moore et al., 2020). The mean age of disease onset of these two patients was 62.5 years, the mean age at death was 67.5 years, and the mean disease duration was 5.0 years. Although no other information is provided about this family, it is unlikely that it overlaps with either of the families described above. Of note, this study included both confirmed mutation carriers, as well as family members who were assumed to be carriers based on their clinical phenotype.

This variant was absent from the gnomAD variant database (gnomAD v4.1.0, Nov 2024).

Neuropathology

A post-mortem brain study of the original UK carrier showed extensive neuronal loss, gliosis, and tau pathology, for which a semi-quantitative regional assessment is detailed in the original report (Iovino et al., 2014). In brief, there was significant neuronal loss in the frontal and parietal cortices, caudate nucleus, and hippocampal subregions CA3 and CA4. Ballooned neurons were prominent in the cingulate gyrus. Phosphorylated tau deposits were present in neurons and glia, and 4-repeat (4R) tau was more prevalent than 3R tau as as assessed by immunohistochemistry. All six tau isoforms were expressed, with increases in 1N4R and 0N4R, compared to a control, as measured by immunoblotting. Moreover, various types of neuronal inclusions, as well as tufted astrocytes and oligodendroglial inclusions, were observed. No TDP-43, Aβ, or α-synuclein pathology was found.

Consistent with the cell loss observed in the post-mortem analysis, this carrier’s CT scan at age 65 showed bilateral cortical atrophy. SPECT imaging showed normal dopamine transporter uptake, however. At age 67, despite normal blood and cerebrospinal fluid analyses, a repeat CT scan confirmed progression of cerebral atrophy, and EEG showed cortical dysfunction based on the presence of intermittent slow waves in the right hemisphere.

Brain imaging of additional carriers has provided further insights. The first sibling from the Italian family case series had ventricular dilatation and supratentorial atrophy as detected on a CT scan at age 60 (Pozzi et al., 2024). In addition, an FDG-PET scan revealed frontotemporal hypometabolism, more pronounced on the right side. An MRI of the second sibling revealed left predominant frontotemporal and hippocampal atrophy. FDG-PET imaging confirmed hypometabolism in the left frontotemporal region. The third sibling’s brain MRI revealed significant atrophy of the right temporal pole, with marked progression 14 months later, expanding into additional brain areas. FDG-PET imaging at the initial exam showed hypometabolism in the right fronto-parietal-temporal areas. The fourth sibling’s MRI showed mild frontal and temporal atrophy on the left side, and FDG-PET imaging indicated left-side fronto-temporal hypometabolism. A follow-up MRI scan 19 months later demonstrated brain atrophy progression.

Biological Effect

This variant lies in the second repeat domain of the MAPT microtubule assembly domain. Microtubule assembly was evaluated using recombinant K298E protein, and it was found to be reduced compared to wild-type protein, suggesting perturbations in K298E tau’s interaction with microtubules (Iovino et al., 2014).

K298E appears to also alter tau fibril formation, without promoting aggregation. In K298E-expressing HEK293T cells that were exposed to fibrils of wild-type K18 tau peptides, which are aggregation-prone, tau did not accumulate, indicating a lack of seeding and tau inclusion formation (Strang et al., 2018). Tau aggregation kinetics were also measured in another study, and while lag time was not significantly different from wild-type, it was numerically higher in K298E samples (Sun et al., 2023). K298E tau had the largest variation in lag time of all 37 variants examined, although variability was not high for other kinetics parameters (i.e., amyloid formation rate constant and amplitude).

The strong effect on lag time may be related to the loss of acetylation at the K298 site (Oct 2023 news; Chakraborty et al., 2023). In vitro, K298 was acetylated when tau was in the presence of microtubules, suggesting it may be acetylated in vivo. When K298 was substituted with a glutamine which, like glutamic acid is not a substrate for acetylation, the aggregation of 4R tau stalled for several days. Moreover, in cryoEM-determined structures of tau fibrils, the positively charged K298 was observed to reach in, toward the core of the protofibril fold, to form an electrostatic bond with a negatively charged aspartic acid, stabilizing the fibril. (The fibrils in this study came from non-carrier patients with corticobasal degeneration, a 4R tauopathy).

Consistent with these findings, Sun and colleagues measured the structural properties of tau fibrils in vitro and found that they were affected by the K298E mutation (Sun et al., 2023). This experiment used the full-length 0N4R splice isoform as a backbone for a trypsin digestion assay and found that fragment profile of K298E tau differed from that of wild-type tau.

Also of note, K298E lies in a region of MAPT that regulates splicing of exon 10. Human neural stem cells expressing K298E had a higher ratio of 4R to 3R tau isoforms than cells expressing wild-type MAPT (Iovino et al., 2014). This was also observed in RNA measured from the proband’s cortex as compared to a control, as well as in induced neurons from the proband’s skin fibroblasts. As noted above, 4R reactivity was also observed to a higher extent than 3R in the proband’s brain.

K298E’s PHRED-scaled CADD score, which integrates diverse information in silico, is 31, above the commonly used threshold of 20 for predicting deleteriousness (CADD v1.7, Apr 2024).

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References

News Citations

1. Acetylation Accelerates Aggregation of 3R, but Not 4R, Tau 6 Oct 2023

Paper Citations

1. Iovino M, Pfisterer U, Holton JL, Lashley T, Swingler RJ, Calo L, Treacy R, Revesz T, Parmar M, Goedert M, Muqit MM, Spillantini MG. The novel MAPT mutation K298E: mechanisms of mutant tau toxicity, brain pathology and tau expression in induced fibroblast-derived neurons. Acta Neuropathol. 2014 Feb;127(2):283-95. Epub 2013 Nov 30 PubMed.
2. Pozzi FE, Aprea V, Giovannelli G, Lattuada F, Crivellaro C, Bertola F, Castelnovo V, Canu E, Filippi M, Appollonio I, Ferrarese C, Agosta F, Tremolizzo L. Clinical and neuroimaging characterization of the first frontotemporal dementia family carrying the MAPT p.K298E mutation. Neurogenetics. 2024 Jul;25(3):215-223. Epub 2024 Apr 9 PubMed.
3. Moore KM, Nicholas J, Grossman M, McMillan CT, Irwin DJ, Massimo L, Van Deerlin VM, Warren JD, Fox NC, Rossor MN, Mead S, Bocchetta M, Boeve BF, Knopman DS, Graff-Radford NR, Forsberg LK, Rademakers R, Wszolek ZK, van Swieten JC, Jiskoot LC, Meeter LH, Dopper EG, Papma JM, Snowden JS, Saxon J, Jones M, Pickering-Brown S, Le Ber I, Camuzat A, Brice A, Caroppo P, Ghidoni R, Pievani M, Benussi L, Binetti G, Dickerson BC, Lucente D, Krivensky S, Graff C, Öijerstedt L, Fallström M, Thonberg H, Ghoshal N, Morris JC, Borroni B, Benussi A, Padovani A, Galimberti D, Scarpini E, Fumagalli GG, Mackenzie IR, Hsiung GR, Sengdy P, Boxer AL, Rosen H, Taylor JB, Synofzik M, Wilke C, Sulzer P, Hodges JR, Halliday G, Kwok J, Sanchez-Valle R, Lladó A, Borrego-Ecija S, Santana I, Almeida MR, Tábuas-Pereira M, Moreno F, Barandiaran M, Indakoetxea B, Levin J, Danek A, Rowe JB, Cope TE, Otto M, Anderl-Straub S, de Mendonça A, Maruta C, Masellis M, Black SE, Couratier P, Lautrette G, Huey ED, Sorbi S, Nacmias B, Laforce R Jr, Tremblay ML, Vandenberghe R, Damme PV, Rogalski EJ, Weintraub S, Gerhard A, Onyike CU, Ducharme S, Papageorgiou SG, Ng AS, Brodtmann A, Finger E, Guerreiro R, Bras J, Rohrer JD, FTD Prevention Initiative. Age at symptom onset and death and disease duration in genetic frontotemporal dementia: an international retrospective cohort study. Lancet Neurol. 2020 Feb;19(2):145-156. Epub 2019 Dec 3 PubMed.
4. Strang KH, Croft CL, Sorrentino ZA, Chakrabarty P, Golde TE, Giasson BI. Distinct differences in prion-like seeding and aggregation between Tau protein variants provide mechanistic insights into tauopathies. J Biol Chem. 2018 Feb 16;293(7):2408-2421. Epub 2017 Dec 19 PubMed.
5. Sun KT, Patel T, Kang SG, Yarahmady A, Srinivasan M, Julien O, Heras J, Mok SA. Disease-Associated Mutations in Tau Encode for Changes in Aggregate Structure Conformation. ACS Chem Neurosci. 2023 Dec 20;14(24):4282-4297. Epub 2023 Dec 6 PubMed.
6. Chakraborty P, Rivière G, Hebestreit A, de Opakua AI, Vorberg IM, Andreas LB, Zweckstetter M. Acetylation discriminates disease-specific tau deposition. Nat Commun. 2023 Sep 22;14(1):5919. PubMed.

Further Reading

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