Overview

Pathogenicity: Frontotemporal Dementia Spectrum : Uncertain Significance
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PP3, BS1, BS2
Clinical Phenotype Studied: rtvFTD, Apraxia of Speech, Corticobasal Syndrome, Corticobasal Degeneration, svPPA, Progressive Supranuclear Palsy, Semantic Dementia, nfvPPA, Amyotrophic Lateral Sclerosis, Posterior Cortical Atrophy
Position: (GRCh38/hg38):Chr17:46018707 G>A
Position: (GRCh37/hg19):Chr17:44096073 G>A
Transcript: NM_005910; ENST00000351559
dbSNP ID: rs63750869
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GTC to ATC
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 12

Findings

This variant has been identified in several individuals with a variety of neurological disorders within the frontotemporal dementia (FTD) spectrum. Although ages at onset of disease vary, they are most often late in midlife. Of note, V363I may have reduced penetrance—it has been identified in aged, unaffected carriers within families, and its frequency in the gnomAD public genetic variant database is higher than for most pathogenic variants with an autosomal dominant inheritance pattern.

V363I was first reported in a woman from Spain presenting with the nonfluent variant of primary progressive aphasia (nfvPPA) at the age of 69 (Munoz et al., 2007). By age 75 her language difficulties had progressed such that she was nearly mute, and she had also developed gait and swallowing disturbances. Her father had reportedly exhibited late-onset aphasia and apraxia. A mutation-carrying sibling showed no abnormalities at age 70. The mutation was absent in 194 control individuals from a similar genetic background.

Another carrier, an Italian woman, was also diagnosed with nfvPPA, as well as apraxia of speech (Rossi et al., 2013; Rossi et al., 2014). She also had early motor symptoms that worsened and developed phenotypes indicative of corticobasal syndrome (CBS), with speech impairment being her first and most pronounced problem. Her age at onset was 55 years. In addition, two other women of European ancestry were diagnosed with CBS (Ahmed et al., 2019).  One of them was diagnosed with PPA, probable CBS, and left-sided parkinsonism in her late 50s. The disease progressed to the point where she could not talk and had severe difficulty swallowing. She died at age 62 and corticobasal degeneration was confirmed at autopsy. She had no known family history of dementia.

Some carriers’ phenotypes, however, diverge more widely. For example, a few individuals have been diagnosed with predominantly motor disorders, such as amyotrophic lateral sclerosis (ALS) in a carrier from the U.S. (Petrozziello et al., 2022) and the Richard Syndrome subtype of progressive supranuclear palsy (PSP-RS) in a Chinese female carrier (Ng et al., 2024). The latter had vertical supranuclear gaze palsy, falls, parkinsonism, axial rigidity, pseudobulbar affect, speech issues, dysphagia, and impulsiveness.

Moreover, at least two carriers have been reported to have posterior cortical atrophy (PCA), a phenotype most often associated with Alzheimer's disease. One was an Italian woman whose symptoms emerged at age 51 and included mild cognitive impairment with visual agnosia and left spatial hemineglect (Rossi et al., 2013; Rossi et al., 2014). The other carrier was a Brazilian woman who fulfilled the criteria for PCA and was also diagnosed with probable CBS overlapping with possible PSP with ocular motor dysfunction (Parmera et al., 2023). Starting at age 47 she developed progressive slow gait, visuospatial difficulties, rigidity, and loss of dexterity. She also had left‐sided parkinsonism and hemi-neglect, as well as left upper limb dystonia, and vertical supranuclear gaze palsy with slowed horizontal saccades.

Also of note, diagnoses have sometimes been uncertain and varied between research groups. For example, the second individual identified as carrying V363I was an Italian woman who presented with a severe difficulty in oral naming and identifying faces (Bessi et al., 2010). Her age at onset was 46 years and later symptoms included disorientation, memory loss, judgement and problem-solving difficulties; loss of insight, hyperorality, and perseveration. She was diagnosed with semantic dementia (SD), a.k.a. the semantic variant of primary progressive aphasia (svPPA). However, this carrier was subsequently described as having right temporal variant FTD (rtvFTD), given the right-side predominance of her anterior temporal atrophy (Villa et al., 2024). Indeed, this carrier may have failed to meet more recent diagnostic criteria for “true” SD/svPPA, a condition which may not have an autosomal dominant genetic etiology, as suggested in a preprint (Henderson et al., 2024). 

A lack of family history of disease in some affected carriers, as well as the identification of aged, unaffected carriers in some families, suggests V363I has reduced penetrance. For example, V363I was found in several unaffected members of the family of a female carrier diagnosed with early onset FTD (Anfossi et al., 2011; bvFTD, according to Villa et al., 2024), including  her 85-year-old mother and a 63-year-old sister.  Moreover, the mother of the Brazilian carrier described above was also a carrier with no neurological symptoms at age 70 (Parmera et al., 2023), as was the 70-year-old sibling of the Spanish carrier (Munoz et al., 2007).

Also, the global frequency of this variant in the public variant database gnomAD is relatively high, 0.000025, including 41 heterozygotes of various ancestries (gnomAD v.4.1.0, April 2024).

A large international retrospective cohort study, conducted through the Frontotemporal Dementia Prevention Initiative and published literature, listed three families with four V363I carriers (Moore et al., 2020, suppl 1). Two presented with svPPA, one with nfvPPA, and one with CBS. The mean age of disease onset was 61.5 years and the mean duration of disease was 5.0 years. The degree of overlap with the carriers described above is unknown. Of note, this study included both confirmed mutation carriers and family members who were assumed to be carriers based on their clinical phenotype.

Neuropathology
Consistent with the clinical heterogeneity described above, post-mortem and imaging observations have revealed neuropathological diversity among carriers.

Neuropathology in post-mortem tissue from a carrier diagnosed with CBS was consistent with corticobasal degeneration (CBD) (Ahmed et al., 2019). In cortical and subcortical areas, widespread thread-like aggregates containing the 4-repeat (4R) tau isoform were observed, as well as achromatic neurons and astrocytic plaques. Affected areas included frontal, parietal, cingular, and motor cortices, as well as the globus pallidus and substantia nigra. Cortical pathology was characterized by astrocytic plaques, abundant pretangles, ballooned neurons, and neuropil threads. Threads and pretangles were also seen in basal ganglia. White matter pathology included widespread threads and coiled bodies also involving the brainstem. Unexpectedly, the hippocampus was also affected. Of note, in cortical areas, a moderate number of diffuse Aβ deposits and cored plaques were observed and, in the globus pallidus, TDP43 inclusions.

Neuroimaging data from several carriers are also available and reveal heterogeneity. For example, longitudinal observations of a patient with nfvPPA showed reduced blood flow in the left frontotemporal cortex (SPECT), followed by predominantly left frontal atrophy (MRI), and subsequently mild hypometabolism in the left parietal lobe when CBS-like symptoms set in (Rossi et al., 2014). In contrast, in the same study, a patient diagnosed with PCA showed alterations in the right parietal and temporal regions as assessed by MRI, and hypometabolism in both left and right posterior temporo-occipital cortices, as well as in the right posterior frontoparietal cortex.

Additional imaging studies have shown bilateral parietal atrophy in a patient with CBS (Ahmed et al., 2019), and right temporopolar atrophy in a patient with an uncertain svPPA/rtvFTD diagnosis (Bessi et al., 2010; Villa et al., 2024). The Brazilian carrier with CBS/PSP/PCA had atrophy in right parieto‐occipital regions and hypometabolism in the right frontal, parietal and occipital lobes, as well as the right striatum (Parmera et al., 2023). This carrier was also found to be negative for amyloid deposition using PET imaging.

The extent of pathology also varies widely, probably in part, due to differences in disease stage. For example,  while a carrier with PSP-RS was reported as having a normal MRI scan (Ng et al., 2024), another with FTD at an advanced stage had massive cortical and subcortical atrophy (Anfossi et al., 2011).

Biological Effect
The valine at position 363, a highly conserved amino acid, resides in the fourth repeat of tau’s microtubule assembly domain, immediately adjacent to PGGG, a motif involved in microtubule binding and aggregation. Moreover, 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).

V363I is a conservative substitution, however, and its effects in experimental assays have been mixed. For example, in a cell-free assay, V363I did not reduce microtubule assembly. In fact, the mutant protein fueled the formation of slightly longer microtubules at a faster rate than wildtype tau (Rossi et al., 2014). Moreover, in an assay using human embryonic kidney (HEK293T) cells in the presence of paclitaxel, the 0N4R mutant isoform resulted in decreased binding of tau to microtubules (Xia et al., 2019), while the 0N3R mutant isoform increased microtubule binding (Xia et al., 2023). 

Experiments probing V363I’s effects on aggregation have also yielded unclear results. In transgenic Caernohabditis elegans expressing the 2N4R isoform of either wildtype or mutant tau in neurons, researchers detected hyperphosphorylated tau, particularly at S202/T205 (AT8), in worms expressing the mutant protein (Morelli et al., 2018). Also, higher levels of mutant tau were detected in detergent-insoluble and formic acid-insoluble fractions, suggesting accumulation in cell membranes and insoluble assemblies. However, oligomerization of the mutant protein was similar to that of wildtype tau and AT8-positive mutant tau was found in monomeric form more often than AT8-positive wildtype tau.   

In cultured cells, both 0N4R (Xia et al., 2019) and 0N3R (Xia et al., 2023) mutant tau isoforms showed modest levels of aggregation which did not increase in the presence of K18 or K19, tau fragments that seed aggregation via amyloidogenic hexapeptide motifs. Moreover, in cell-free assays, mutant tau was observed to polymerize relatively quickly, but slow down rapidly, resulting in very few aggregates, including mostly oligomers, rarely protofibrils, and no fibrils (Rossi et al., 2014). A subsequent in vitro study reported monomeric mutant tau in solution behaved similarly to wildtype tau as an intrinsically disordered protein (De Luigi et al., 2022). Moreover, although V363I tau did form β-sheet structures, the kinetics were slow and the resulting fibrils were short and scarce compared to those formed by tau carrying the pathogenic mutation P301L.

Effects on other cellular processes have also been reported. For example, a study in transgenic C. elegans neurons revealed an apparent reduction in sensitivity to the nicotinic acetylcholine receptor agonist levamisole, suggesting defective postsynaptic transmission (Morelli et al., 2018). Moreover, a study of peripheral blood cells and fibroblasts from two human carriers showed elevated DNA copy number variations (Rossi et al., 2013). The authors suggested this effect might be due to the disruption of tau’s role in chromatin stabilization.

While the lifespan of transgenic worms carrying human V363I tau was similar to that of worms carrying human wildtype tau (Morelli et al., 2018), a moderate decrease in viability was reported in human neuroblastoma cell line SH-SY5Y carrying the mutation (De Luigi et al., 2022).

In silico algorithms that predict deleteriousness have also yielded mixed results. SIFT, PolyPhen2, MutationTaster, ClinPred, and Primate AI categorized the variant as tolerated and/or benign. REVEL gave an uncertain prediction, while FATHMM-XF, M-CAP, and CADD yielded damaging predictions (Ahmed et al., 2019; Ng et al., 2024). The variant's PHRED-scaled CADD score was 23.6, above the commonly used threshold of 20 (CADD v1.7, April 2024). V363I was classified as pathogenic by Ng and colleagues (Ng et al., 2024).

Pathogenicity

Frontotemporal Dementia Spectrum : Uncertain Significance*

*This variant may have reduced penetrance, a condition outside the scope of the ACMG-AMP guidelines. Also, clinical phenotypes varied widely between carriers.

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

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2. 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.
3. Rossi G, Bastone A, Piccoli E, Morbin M, Mazzoleni G, Fugnanesi V, Beeg M, Del Favero E, Cantù L, Motta S, Salsano E, Pareyson D, Erbetta A, Elia AE, Del Sorbo F, Silani V, Morelli C, Salmona M, Tagliavini F. Different mutations at V363 MAPT codon are associated with atypical clinical phenotypes and show unusual structural and functional features. Neurobiol Aging. 2014 Feb;35(2):408-17. Epub 2013 Sep 7 PubMed.
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7. Parmera JB, Coutinho AM, Guimarães TG, Yuri Silvestre Yamamoto J, Takada LT, Nitrini R, Barbosa ER, Brucki SM. Expanding MAPT p.V363I Mutation Phenotype: An Overlapping of PSP-CBS and Posterior Cortical Atrophy. Mov Disord Clin Pract. 2023 Apr;10(4):716-718. Epub 2023 Feb 14 PubMed.
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13. 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.
14. 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.
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Further Reading

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