Overview

Pathogenicity: Frontotemporal Dementia Spectrum : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PS4, PM1, PM2, PP3
Clinical Phenotype Studied: Parkinsonism
Position: (GRCh38/hg38):Chr17:46018710 C>T
Position: (GRCh37/hg19):Chr17:44096076 C>T
Transcript: NM_005910; ENST00000351559
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CCT to TCT
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 12

Findings

Carriers of this mutation have a wide variety of clinical phenotypes that fall within the frontotemporal dementia (FTD) spectrum, including behavioral symptoms and cognitive decline characteristic of the behavioral variant of FTD (bvFTD), parkinsonism, and motoneuron alterations typical of amyotrophic lateral sclerosis (ALS). High variability even within the same family has been reported. Of note, multiple families—which included multiple affected carriers within each family—showed transmission of disease consistent with autosomal dominant inheritance. Moreover, several non-carriers in these families, including members of older generations, were unaffected. However, segregation with disease could not be confirmed because the ages of the unaffected non-carriers were not reported (to fulfill the segregation criterion, Alzforum requires the ages of healthy non-carriers to be at least two standard deviations greater than the family’s mean age at onset).

This mutation was first identified in an Italian individual with apparently sporadic early onset FTD (Rossi et al., 2012). At the age of 47 he developed memory loss and mood changes, followed by apathy, disinhibition, and behavioral changes. In a subsequent study, his disorder was described as bvFTD (Moore et al., 2020). He did not have a family history of dementia (Rossi et al., 2012). His father died from lung cancer at the age of 75 and his 76-year-old mother was alive and cognitively healthy at the time of the report. Dementia was also notably absent in five paternal aunts and uncles and in six maternal aunts and uncles. The proband was a mutation carrier, but his unaffected mother and brother were not.

The MAPT P364S mutation was subsequently detected in two sisters from Slovenia with a clinical syndrome on the FTD spectrum spectrum (Popović et al., 2014), subsequently described as bvFTD (Moore et al., 2020). In their 50s, both developed cognitive decline, depression, bradykinesia, rigidity, and a forward-bent gait (Popović et al., 2014). One was noted to have frequent falls and the other to have symptoms of motor neuron disease, including fasciculations and muscle atrophy. Both died of respiratory insufficiency within a few years of onset. Their mother reportedly had also developed a forward-bent gait and died with dementia at the age of 48. A follow-up study of this family, spanning six generations, analyzed four affected carriers (Štrafela et al., 2018). Three presented with cognitive decline, two with parkinsonism, and three with motor neuron disease. Three individuals developed respiratory insufficiency and died within two years of disease onset, between the ages of 55 and 66 years. This study reported several unaffected non-carriers, including one three generations above the youngest members.

Five French families carrying P364S were also reported. Two families with multiple affected individuals across two or three generations, including two affected carriers in each, had disorders with symptoms that overlapped with those of ALS and FTD, with the main symptom being progressive respiratory failure (Favier et al., 2025). Gait disturbances, bulbar signs including swallowing disorders and dysarthria, pyramidal signs, and cognitive and behavioral alterations were observed. In addition, signs of mild denervation were revealed by electroneuromyogram and three patients had diaphragmatic paralysis. Initial diagnoses of atypical motor neuron disease were given to six patients. However, prolonged survival, early respiratory failure with potential recovery, cerebellar signs, and atypical electroneuromyograms were not supportive of ALS. Even within each family, clinical phenotypes were very variable.

Interestingly, the three additional French families carrying this mutation were identified by an analysis of whole-exome sequences from 470 ALS patients (De Bertier et al., 2025). In one family, two affected cousins were identified as carriers, whereas single carriers were identified in the other two families. Members of all three families developed ALS between the ages of 40 and 70 years, with a mean age of onset of 54 years and a mean survival of 44.5 months. As in other families described above, the clinical phenotypes varied, even within a single family, and included some rare ALS presentations such as respiratory onset and “dropped head” syndrome. Although all patients had lower motor neuron dysfunction—including cramps, fasciculations, and amyotrophy—typical ALS alterations, such as chronic neurogenic changes and abnormal spontaneous activity, were observed only one or two years after symptom onset. Two carriers had cognitive deficits, including executive dysfunction typical of ALS, as well as memory impairments.

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

Neuropathology
The first detailed neuropathological analysis of P364S carriers appears in the original report of the two sisters from Slovenia, and indicated lesions consistent with tauopathy (Popović et al., 2014). Neuronal loss and reactive gliosis were prominent in the nucleus basalis of Meynert, substantia nigra, locus coeruleus, motor cortex, and the anterior horn of the spinal cord. Neuronal tau inclusions were prominent in many brain regions. Globose neurofibrillary tangles were the most abundant type, with some flame-shaped neurofibrillary tangles as well, the latter mostly restricted to the hippocampus. Some Pick body-like inclusions were seen in one case.

A unique characteristic of these sisters’ pathology, later observed in additional mutation carriers (Štrafela et al., 2018, Favier et al., 2025), was the presence of composite neuronal tau inclusions with distinct core and peripheral regions (Popović et al., 2014).  These inclusions contained tau isoforms with three microtubule binding repeats (3R) and four (4R) tau, with 3R tau in the core and periphery, and 4R tau only in the periphery. In the sisters, this pathology was seen most frequently in subiculum, subthalamic nucleus, thalamus, motor cortex, and substantia nigra.

In a subsequent study that analyzed the brains of four carriers in this family, neuronal tau inclusions of almost all known types, including composite tau inclusions, were reported as widespread (Štrafela et al., 2018). As previously described, mutant tau was composed of 3R and 4R isoforms, with a slight predominance of 3R tau. Fibrillary tau inclusions had a similar distribution throughout the brain and spinal cord and mostly affected neurons. The most frequent neuronal tau inclusions were large globose neurofibrillary tangles similar to those found in patients with progressive supranuclear palsy, but containing both 3R and 4R tau, instead of predominantly 4R tau. Ghost tangles, thought to be residual aggregates in brain regions affected early in the disease course, were especially abundant in the Meynert nucleus, substantia nigra, hippocampus, locus coeruleus, brain stem nuclei and the anterior horns of the spinal cords. As assessed by electron microscopy, CNTIs had fuzzy straight fibrils in the core and paired twisted tubules at the periphery.

In at least two carriers, Pick-like inclusions were observed. In one case, swollen neurons and Pick bodies, containing almost exclusively 3R tau, were found in brain regions typically affected by Pick’s disease (Štrafela et al., 2018), and in the other, large Pick-like inclusions were observed in Betz cells of the primary motor cortex (De Bertier et al., 2025).

In a carrier diagnosed with ALS, hyperphosphorylated tau (AT8 antibody) was prominent in the motor cortex with Lewy body-like inclusions (De Bertier et al., 2025). Tau pathology was also observed in the dentate gyrus of the hippocampus, the substantia nigra, and the frontal cortex. Using several tau antibodies, the researchers identified neurofibrillary tangles, pretangles, oligodendroglial inclusions, and aggregates suggestive of glial plaques. Interestingly, in muscle, a C-terminal cleaved form of tau, truncated at aspartate 421, was identified (Tau-C3 antibody) in round structures. As noted by the authors, this tau fragment has been associated with Alzheimer’s disease tauopathy (De Bertier et al., 2025).

In a patient with respiratory failure as the main phenotype, neuronal loss and reactive gliosis were observed in cortical and subcortical regions, cranial nerves, and the anterior horn of the spinal cord which could explain this individual’s diaphragm paralysis (Favier et al., 2025). Of note, in this patient (Favier et al., 2025), as well as another (Štrafela et al., 2018), frontotemporal atrophy was mild, possibly due to respiratory dysfunction leading to a short duration of disease.

Biological Effect
P364, in tau’s fourth microtubule-binding repeat, is highly conserved across species and part of PGGG, a motif found in all four microtubule-binding repeats. In vitro, mutant tau exhibited reduced ability to promote microtubule assembly compared with wild-type tau (Rossi et al., 2012).

Under some circumstances, P364S may also affect tau aggregation. Indeed, it has been suggested that the stretch of amino acids between positions 353 and 368 acts as a regulator of the formation of fibrous tau structures like those found in Alzheimer’s disease (Shimonaka et al., 2020). Moreover, an early in vitro study reported the mutant  increased the rate of tau aggregation compared to wildtype tau (Rossi et al., 2012).

However, in most cases, this mutation does not appear to fuel tau aggregation. For example, P332S did not influence the propensity of tau to aggregate in human embryonic kidney (HEK) cells with or without preformed seeds composed of the wildtype K18 tau peptide (Strang et al., 2018). Interestingly, this is in contrast to P301S, the analogous mutation in the PGGG motif of the second microtubule binding domain.

A subsequent study showed that three PGGG mutants, including P364S, have different effects on tau aggregation depending on the molecule used to induce aggregation (Ingham et al., 2022).  Consistent with Strang and coworkers’ study, in the presence of most aggregation inducers, P364S tau had similar, or even weaker, effects on aggregation than wildtype tau. For example, the mutation had no detectable effect on aggregation induced by arachidonic acid. In the case of aggregation induced by polyphosphates P100 and P700, mutant tau formed fewer filaments than wildtype tau, although the filaments were longer. Lastly, when using non-coding RNAs (sRNA and lRNA) as inducers, P364S tau reduced the numbers and/or lengths of tau filaments compared to those formed with wildtype tau.

The mutant protein may have other deleterious effects. For example, impaired mitochondrial mobility and abnormal subcellular tau distribution were detected in cultured motor neurons expressing P364S (De Bertier et al., 2025). Clusters of mutant tau, acetylated tubulin, and stalled mitochondria were observed in the cells’ neurites. As suggested by the authors, mutant tau truncated at aspartate 421 may contribute to these abnormalities, as well as to mitochondrial damage and synaptic failure at neuromuscular junctions.

Also of note, in post-mortem brain tissue from one carrier, PICALM—a clathrin-adaptor protein involved in endocytosis and autophagy—was reduced in its soluble form and co-precipitated with phosphorylated tau (PHF-1) (Ando et al., 2020).  In addition, increased chromosomal instability and copy-number variations have been reported in lymphocytes and fibroblasts of mutation carriers (Rossi et al., 2013).

The molecular underpinnings for these effects remain unclear, but in silico modeling suggests P364S may modify tau folding (De Bertier et al., 2025). Interestingly, the predicted mutant structure shares some similarity with the predicted folding of tau carrying the pathogenic P301L mutation.

This variant's PHRED-scaled CADD score (25.6), 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 : Pathogenic

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

Mutations Citations

1. MAPT P301L

Paper Citations

1. Rossi G, Bastone A, Piccoli E, Mazzoleni G, Morbin M, Uggetti A, Giaccone G, Sperber S, Beeg M, Salmona M, Tagliavini F. New mutations in MAPT gene causing frontotemporal lobar degeneration: biochemical and structural characterization. Neurobiol Aging. 2012 Apr;33(4):834.e1-6. Epub 2011 Sep 22 PubMed.
2. 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.
3. Popović M, Fabjan A, Mraz J, Magdič J, Glavač D, Zupan A, Novak MD, Bresjanac M. Tau protein mutation P364S in two sisters: clinical course and neuropathology with emphasis on new, composite neuronal tau inclusions. Acta Neuropathol. 2014 Jul;128(1):155-7. Epub 2014 May 13 PubMed.
4. Štrafela P, Pleško J, Magdič J, Koritnik B, Zupan A, Glavač D, Bresjanac M, Popović M. Familial tauopathy with P364S MAPT mutation: clinical course, neuropathology and ultrastructure of neuronal tau inclusions. Neuropathol Appl Neurobiol. 2018 Oct;44(6):550-562. Epub 2018 Jan 7 PubMed.
5. Favier M, Formaglio M, Cosson A, Claudé F, Fauret-Amsellem AL, Clot F, Dionet E, Bereau M, Piard J. Respiratory failure as main presentation sign of MAPT-related disorder. J Neurol. 2025 Jan 17;272(2):155. PubMed.
6. De Bertier S, Lautrette G, Amador MD, Miki T, Boillée S, Lobsiger CS, Bohl D, Darios F, Machat S, Duchesne M, Vourc'h P, Fauret-Amsellem AL, Corcia P, Guy N, Couratier P, Seilhean D, Millecamps S. MAPT mutations in amyotrophic lateral sclerosis: clinical, neuropathological and functional insights. J Neurol. 2025 Mar 18;272(4):272. PubMed.
7. Shimonaka S, Matsumoto SE, Elahi M, Ishiguro K, Hasegawa M, Hattori N, Motoi Y. Asparagine residue 368 is involved in Alzheimer's disease tau strain-specific aggregation. J Biol Chem. 2020 Oct 9;295(41):13996-14014. Epub 2020 Aug 5 PubMed.
8. Ingham DJ, Hillyer KM, McGuire MJ, Gamblin TC. In vitro Tau Aggregation Inducer Molecules Influence the Effects of MAPT Mutations on Aggregation Dynamics. Biochemistry. 2022 Jul 5;61(13):1243-1259. Epub 2022 Jun 22 PubMed.
9. Ando K, De Decker R, Vergara C, Yilmaz Z, Mansour S, Suain V, Sleegers K, de Fisenne MA, Houben S, Potier MC, Duyckaerts C, Watanabe T, Buée L, Leroy K, Brion JP. Picalm reduction exacerbates tau pathology in a murine tauopathy model. Acta Neuropathol. 2020 Apr;139(4):773-789. Epub 2020 Jan 10 PubMed.
10. Rossi G, Conconi D, Panzeri E, Redaelli S, Piccoli E, Paoletta L, Dalprà L, Tagliavini F. Mutations in MAPT gene cause chromosome instability and introduce copy number variations widely in the genome. J Alzheimers Dis. 2013;33(4):969-82. PubMed.

Other Citations

1. Strang et al., 2018

Further Reading

No Available Further Reading