Overview

Pathogenicity: Frontotemporal Dementia Spectrum : Not Classified, Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP3
Clinical Phenotype Studied: Alzheimer's Disease, Frontotemporal Dementia, Tauopathy consistent with Pick's Disease
Position: (GRCh38/hg38):Chr17:46018726 A>T
Position: (GRCh37/hg19):Chr17:44096092 A>T
Transcript: NM_005910; ENST00000351559
dbSNP ID: rs63751264
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: AAA to ATA
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 12

Findings

Although the clinical phenotype of only one carrier of this mutation has been described in the literature, multiple studies have examined its biological effects using isolated proteins, cell-based assays, and animal models (see Biological Effects below).

K369I was initially identified in a 50-year-old woman of German origin presenting first with depression and dramatic personality changes, followed by loss of cognitive function (Neumann et al., 2001). The patient continued to deteriorate and died at the age of 61. As described below, neuropathology was typical of Pick’s disease. Family history was unavailable, and therefore it was not possible to assess whether the mutation segregated with disease.

This variant was also reported in an international, retrospective cohort study that collected data from the Frontotemporal Dementia Prevention Initiative and the published literature (Moore et al., 2020, suppl tables 5-6). The single carrier reported had the same age at onset and age at death as the German carrier, but they were reported as having Alzheimer’s disease.

This variant was absent from the gnomAD variant database (gnomAD v4.1.1, Apr 2024).

Neuropathology

Postmortem examination of the proband's brain showed atrophy, which was most pronounced in the temporal lobes. Numerous tau-positive Pick bodies and Pick cells indistinguishable from those of sporadic Pick's disease were observed in the neocortex, hippocampus, and subcortical brain regions (Neumann et al., 2001). Although tau containing four microtubule-binding repeats (4R tau) was detectable by western blot in this carrier’s brain tissue, Pick bodies were composed only of 3R tau, as is typical for this type of inclusion (de Silva et al., 2006).

Biological Effect

K369 is within the microtubule assembly domain, at the border of the fourth repeat, in a C-terminal pseudorepeat region (PRR) which has been implicated in increasing microtubule binding by reducing the dissociation rate (Niewidok et al., 2016).

Effects on microtubule binding and dynamics have been reported for the K369I substitution, but not under all experimental conditions. In the original report of the mutation, recombinant tau proteins with the K369I mutation showed reduced ability to promote microtubule assembly (Neumann et al., 2001). Moreover, a subsequent study using HEK293T cells transfected with mutant tau containing four microtubule-binding repeats (0N4R) revealed reduced microtubule binding in the presence of the microtubule stabilizer paclitaxel (Xia et al., 2019). On the other hand, an in vitro study found no effect of the mutation on microtubule maximum polymerization, rate of polymerization, or lag time (Combs and Gamblin 2012).

Interestingly, in a study using transfected PC12 cells differentiated into neuron-like cells, mutant tau binding to microtubules in axon-like processes was similar to that of wildtype tau, but the mutant protein had higher on- and off-rates as assessed by fluorescence decay after photoactivation (Niewidok et al., 2016). Also, this group reported an aberrant interaction of phosphorylated K369I tau with c-Jun N-terminal kinase- interacting protein 1 (JIP1), a protein that regulates cargo binding to the kinesin transport machinery along microtubules (Ittner et al., 2009, Götz et al., 2010). In transgenic mice, axonal transport was impaired in dopaminergic neurons and in sciatic nerves (Ittner et al., 2008). Moreover, in a study of transgenic flies, microtubule diameters were increased in homozygous, aged flies and axons became progressively fragmented (Law et al., 2022). The axons of heterozygote flies were not fragmented, but abnormal projections were observed.

In contrast, K369I appears to have no effect on, or even reduces, the propensity of tau to aggregate. In vitro studies with isolated proteins indicated mutant tau aggregates less than wildtype tau, as assessed by thioflavin S fluorescence and laser light scattering (Combs and Gamblin). Consistent with these findings, very few and very short filaments were observed by electron microscopy. Moreover, in transfected HEK293T cells, mutant 0N4R tau had no effect on tau aggregation in the presence or absence of exogenous K18 peptides—tau fragments that act as aggregation seeds (Xia et al., 2019). 

Studies of transgenic mice expressing human tau with the K369I mutation in neurons, a.k.a. K3 mice, have revealed pathologies and behavioral phenotypes reminiscent of FTD with parkinsonism (Ittner et al., 2008). Behavioral phenotypes include early-onset memory deficits, and parkinsonism-like features. Neuropathologically, K3 mice have hyperphosphorylated tau aggregates in the cortex and loss of dopaminergic neurons in the striatum. Neurofibrillary tangles, as well as round Pick body-like lesions have been observed with tau phosphorylation patterns similar to those seen in FTD. In addition, amyotrophy without overt neurodegeneration has been reported.

Functional effects at the cellular level have also been reported in these mice. For example, impaired axonal transport (Ittner et al., 2008), and a shift towards burst firing in striatal neurons that correlated with changes in goal-directed behaviors (Mo et al., 2020) were observed. Also, neurons containing pathologically phosphorylated tau were reported to have decreased protein synthesis and multiple proteomic changes, including decreased synthesis of ribosomal proteins (Evans et al., 2019).

Flies expressing human mutant tau instead of Drosophila tau showed progressive memory impairment and some evidence of sleep disruption, but no locomotor deficits (Law et al., 2022). In aged flies, homozygous for the mutation, fragmented axons were observed, and in heterozygous, aged flies, the levels of two synaptic vesicle proteins were decreased.

This variant's PHRED-scaled CADD score (23.2), which integrates diverse information in silico, was above the commonly used threshold of 20 to predict deleteriousness (CADD v1.7, Apr 2024).

Pathogenicity

Frontotemporal Dementia Spectrum : Not Classified*

*This variant fulfilled several 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.

Research Models

A transgenic mouse (K3) expressing human MAPT with K369I driven by the neuron-specific mThy1.2 promoter was generated (Ittner et al., 2008). As described above, these mice have phenotypes and neuropathology that mimic aspects of the disorder observed in the human carrier. The model has been used to study tauopathy in the context of both FTD and AD (see Further Reading). A knock-in fly model that expresses human mutant tau in place of endogenous Drosophila tau has also been generated (Law et al., 2022).

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References

Paper Citations

1. Ittner LM, Fath T, Ke YD, Bi M, van Eersel J, Li KM, Gunning P, Götz J. Parkinsonism and impaired axonal transport in a mouse model of frontotemporal dementia. Proc Natl Acad Sci U S A. 2008 Oct 14;105(41):15997-6002. Epub 2008 Oct 2 PubMed.
2. Law AD, Cassar M, Long DM, Chow ES, Giebultowicz JM, Venkataramanan A, Strauss R, Kretzschmar D. FTD-associated mutations in Tau result in a combination of dominant and recessive phenotypes. Neurobiol Dis. 2022 Aug;170:105770. Epub 2022 May 16 PubMed.
3. Neumann M, Schulz-Schaeffer W, Crowther RA, Smith MJ, Spillantini MG, Goedert M, Kretzschmar HA. Pick's disease associated with the novel Tau gene mutation K369I. Ann Neurol. 2001 Oct;50(4):503-13. PubMed.
4. 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.
5. de Silva R, Lashley T, Strand C, Shiarli AM, Shi J, Tian J, Bailey KL, Davies P, Bigio EH, Arima K, Iseki E, Murayama S, Kretzschmar H, Neumann M, Lippa C, Halliday G, MacKenzie J, Ravid R, Dickson D, Wszolek Z, Iwatsubo T, Pickering-Brown SM, Holton J, Lees A, Revesz T, Mann DM. An immunohistochemical study of cases of sporadic and inherited frontotemporal lobar degeneration using 3R- and 4R-specific tau monoclonal antibodies. Acta Neuropathol. 2006 Apr;111(4):329-40. Epub 2006 Mar 22 PubMed.
6. Niewidok B, Igaev M, Sündermann F, Janning D, Bakota L, Brandt R. Presence of a carboxy-terminal pseudorepeat and disease-like pseudohyperphosphorylation critically influence tau's interaction with microtubules in axon-like processes. Mol Biol Cell. 2016 Nov 7;27(22):3537-3549. Epub 2016 Aug 31 PubMed.
7. Xia Y, Sorrentino ZA, Kim JD, Strang KH, Riffe CJ, Giasson BI. Impaired tau-microtubule interactions are prevalent among pathogenic tau variants arising from missense mutations. J Biol Chem. 2019 Nov 29;294(48):18488-18503. Epub 2019 Oct 24 PubMed.
8. Combs B, Gamblin TC. FTDP-17 tau mutations induce distinct effects on aggregation and microtubule interactions. Biochemistry. 2012 Oct 30;51(43):8597-607. Epub 2012 Oct 18 PubMed.
9. Ittner LM, Ke YD, Götz J. Phosphorylated Tau interacts with c-Jun N-terminal kinase-interacting protein 1 (JIP1) in Alzheimer disease. J Biol Chem. 2009 Jul 31;284(31):20909-16. Epub 2009 Jun 2 PubMed.
10. Götz J, Lim YA, Ke YD, Eckert A, Ittner LM. Dissecting toxicity of tau and beta-amyloid. Neurodegener Dis. 2010;7(1-3):10-2. Epub 2010 Feb 13 PubMed.
11. Mo M, Jönsson ME, Mathews MA, Johnstone D, Ke YD, Ittner LM, Balleine BW, Furlong TM, Camp AJ. K369I Tau Mice Demonstrate a Shift Towards Striatal Neuron Burst Firing and Goal-directed Behaviour. Neuroscience. 2020 Nov 21;449:46-62. Epub 2020 Sep 17 PubMed.
12. Evans HT, Benetatos J, van Roijen M, Bodea LG, Götz J. Decreased synthesis of ribosomal proteins in tauopathy revealed by non-canonical amino acid labelling. EMBO J. 2019 Jul 1;38(13):e101174. Epub 2019 May 22 PubMed.

Further Reading