Overview

Pathogenicity: Frontotemporal Dementia Spectrum : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PS4, PM1, PP1, BP4
Clinical Phenotype Studied: Alzheimer's Disease, Frontotemporal Dementia, Progressive Supranuclear Palsy
Position: (GRCh38/hg38):Chr17:46010418 C>T
Position: (GRCh37/hg19):Chr17:44087784 C>T
dbSNP ID: rs63751011
Coding/Non-Coding: Non-Coding
DNA Change: Substitution
Expected RNA Consequence: Splicing Alteration
Expected Protein Consequence: Isoform Shift
Codon Change: C to T
Genomic Region: Intron 10
Research Models: 6

Findings

The MAPT IVS10+16 C>T intronic mutation is relatively common, found in dozens of families from around the world (Ryan et al., 2022). Individuals with this mutation display a variety of clinical phenotypes within the frontotemporal dementia (FTD) spectrum with variable ages of onset and disease durations, including behavioral variant FTD (bvFTD), progressive supranuclear palsy (PSP), progressive subcortical gliosis (PSG), semantic variant primary progressive aphasia (svPPA), and FTD with parkinsonism. In addition, a few carriers display phenotypes similar to Alzheimer's disease (AD). 

This mutation was originally found in four families (one from Australia, one from the United States, and two from the United Kingdom), two of which had prior evidence of genetic linkage to chromosome 17. Haplotype analysis suggests that these families likely share a common founder, dating back to approximately 1300 AD, indicating a larger shared pedigree (Colombo et al., 2009; Pickering-Brown et al., 2004). The Australian kindred, known as Aus1, had 28 affected members over five generations with a mean age at onset of 53. The U.S. kindred, known as FTD002, had three affected members over two generations with a mean age at onset of 40. The U.K. kindreds, known as Man6 and Man23, had two and 10 affected members in one and two generations, with mean onsets at 48 and 51 years old, respectively (Hutton et al., 1998). Of note, although the authors described the mutation as segregating with disease, unaffected, non-carriers well past the mean age at onset were not reported. In another report, 13 affected carriers from the Man6 and Man23 families, along with six other families from the same region, exhibited prototypical FTD characterized by disinhibition, overactivity, fatuous affect, puerile behavior, stereotypies, and language impairment (Pickering-Brown et al., 2002). 

A large international retrospective cohort study conducted through the Frontotemporal Dementia Prevention Initiative, and including published literature, identified 149 individuals with the IVS10+16 C>T mutation across 48 families (Moore et al., 2020). Of these, 67 percent were diagnosed with bvFTD, while 17 percent exhibited a primary parkinsonian phenotype. The mean age of disease onset was 50.9 years (n=105), the mean age at death was 60.8 years (n=94), and the mean disease duration was 10.5 years (n=66). No other information is provided about these families, and it is unclear to what extent there is overlap with 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.

The IVS10+16 C>T mutation has also been associated with an AD-like phenotype in several families. The largest of these was a Liverpool family from which eight individuals across three generations were reported, with an autosomal-dominant inheritance pattern (Doran et al., 2007). Four male patients (three brothers and a cousin) were initially diagnosed with early-onset AD and later with FTD with parkinsonism linked to chromosome 17 (FTDP-17). They presented with early memory difficulty and anomia, and FTD-like behavioral issues appeared later. Mean onset was 42 years (range 39–46). The four other affected individuals in this family also had early-onset dementia and died in their mid-40s to early 50s. The mutation was confirmed in the proband and one brother (not assessed in the others; Doran et al., 2007; Larner 2009). Similarly, a 58-year-old man from Northwest England was initially diagnosed with early-onset familial AD after a 2-year history of memory deterioration, but later diagnosed with FTDP-17 due to the IVS10+16 C>T mutation (Larner 2008). Two of his older brothers were also diagnosed with early-onset AD in their 40s and died in their 50s, but genetic testing and neuropathology were not conducted. Notably, neither parent had memory issues—the father dying from a myocardial infarction in his 60s, the mother in her early 80s. It is unclear whether this family is related to the aforementioned one. Another man from Liverpool was diagnosed at age 52 with young-onset familial AD and possible PSP, and was later confirmed to carry the IVS10+16 C>T mutation, leading to an FTDP-17 diagnosis (Larner et al., 2009). This individual’s mother was reported to have developed AD in her 50s and died in her 60s; he died of a chest infection at age 56.

Further illustrating the phenotypic heterogeneity across IVS10+16 C>T families, a PSP-like phenotype was observed in a 40-year-old male carrier who presented with fatigue, micrographia, high-pitched voice, oculomotor issues (limited upgaze, slow hypometric saccades), eventually progressing to balance impairment with falls, occasional choking, facial motor impairments, postural instability, and cognitive dysfunction (Morris et al., 2003). He had no relevant family history, and died at age 45. In contrast, PSG was observed in another family, with disease characterized by behavioral abnormalities, cognitive impairment, motor restlessness, and extrapyramidal signs (Goedert et al., 1999). In this PSG-1 family, the IVS10+16 C>T mutation was absent in some unaffected individuals, but their ages were not reported. The mean (n=4) disease onset was 49 years (range, 41-58 years) and disease duration was 12 years. Additionally, cases of semantic variant primary progressive aphasia (n=13) were found in a study of patients with the IVS10+16 C>T mutation identified from PubMed and the China National Knowledge Infrastructure (CNKI) database, with ages of onset ranging from 47 to 64 years (Ma et al., 2025). Only two of the 13 carriers in this study were noted as previously published (Pickering-Brown et al., 2008).

This variant was reported in the gnomAD variant database at a frequency of 0.0000073, including 10 heterozygotes, nine of European (non-Finnish) ancestry (gnomAD v.4.1.0, April 2024). It was absent from a repository of genetic variants from nearly 500 people age 60 or older who had no neurodegenerative pathology at time of death (HEX database, April 2024).

Neuropathology
There is great heterogeneity in the neuropathological presentation of individuals carrying the IVS10+16 C>T mutation, even within families, though hallmarks include frontotemporal atrophy, neuronal and glial tau inclusions—mostly containing the four-repeat tau isoform 4R2N—and loss of pigment in brainstem nuclei (Lantos et al., 2002; Pickering-Brown et al., 2002). A 2021 study used an unsupervised machine learning technique to classify MAPT mutations according to atrophy patterns and clinical phenotype (Young et al., 2021). In this study, all nine of the IVS10+16 C>T analyzed were classified as “temporal subtype," characterized by pronounced atrophy in the hippocampus, amygdala, temporal cortex, and insula. The most common symptoms in this group were amnestic (e.g., impaired episodic memory), unlike those of patients in the “frontotemporal subtype,” who more prominently exhibited executive dysfunction. Interestingly, patients with the R406W were also classified into the temporal subtype.

In taking a closer look at specific patients, one study of four autopsied cases in the Australian kindred (Aus1) showed neuronal loss, gray-matter gliosis, and neuropil vacuolation in both frontal and temporal lobes. Balloon neurons in the cortex were also observed, along with degeneration of the substantia nigra with free melanin. Tau-positive neurons were observed in select brain regions. Amyloid plaques, Lewy bodies, and Pick bodies were not observed (Baker et al., 1997). In the Liverpool family noted above, tau-positive inclusions were found postmortem in the proband, but other microscopic features such as balloon neurons, Pick bodies, and Lewy bodies were not seen (Doran et al., 2007). On computed tomography, brain atrophy was observed in this family, especially around the temporal regions.

Neuropathological findings from other cases and families further illustrate the mutation’s diverse impact. In the PSG-1 family, tau immunostaining was observed in neurons and glia, with ultrastructural analysis revealing tau filaments as irregularly twisted ribbons (Goedert et al., 1999). Ballooned neurons, tufted astrocytes, features resembling Pick bodies, and coiled bodies were also present. Similarly, the individual with PSP-like disease exhibited severe atrophy, particularly in the mediotemporal region and temporal neocortex, along with neuronal and oligodendroglial tau-positive inclusions, neuropil threads, tufted astrocytes, oligodendroglial coiled bodies, and ballooned neurons (Morris et al., 2003). Tau inclusions and diffuse tau staining have also been observed in von Economo neurons and fork cells of the frontoinsular and anterior cingulate cortices in three patients with bvFTD (Lin et al., 2019). These findings highlight the consistent presence of tau pathology across different clinical presentations, despite variations in specific neuropathological features.

Imaging studies provide additional insights into the mutation’s effects. In five individuals carrying the IVS10+16 C>T mutation who were diagnosed with bvFTD, MRI revealed asymmetric atrophy of the anterior and medial temporal lobes—particularly the right medial temporal lobe—as well as the orbitofrontal cortex, right amygdala, and right hippocampus (Whitwell et al., 2005). Similarly, the 58-year-old man with FTD who was initially misdiagnosed with early-onset familial AD, showed bilateral temporal lobe atrophy on MRI (Larner 2008). Another aforementioned individual, who was initially diagnosed with AD at age 50, displayed temporal lobe atrophy on computed tomography two years after symptom onset, which was not evident at initial presentation (Larner 2009). These imaging findings underscore the prominence of temporal lobe involvement in IVS10+16 C>T mutation carriers.

Advanced imaging techniques have further elucidated tau pathology and neuroinflammation in patients with the IVS10+16 C>T mutation. PET imaging with flortaucipir was used to evaluate AD-type tau aggregates in two individuals (aged 44 and 58) with mild cognitive impairment who had the IVS10+16 C>T mutation (Tsai et al., 2019). Ligand uptake was observed bilaterally in the basal ganglia in one patient and in the frontal poles and right lateral temporal lobe in the other, though relative uptake was low, possibly reflecting early disease stages. Additionally, PET imaging with [11C]-PK-11195 to assess microglial activation and [18F]-AV-1451 to evaluate tau burden, combined with MRI, in a presymptomatic IVS10+16 C>T carrier revealed no atrophy or protein aggregation, but showed signs of neuroinflammation in frontotemporal regions (Bevan-Jones et al., 2019). These findings suggest that neuroinflammation may precede overt neuropathological changes in mutation carriers.

Of note, a large pedigree from New Zealand with bvFTD is expected to shed additional light on neuropathological progression (Ryan et al., 2022). Asymptomatic members of this family are currently under longitudinal investigation in the New Zealand Genetic Frontotemporal Dementia Study (FTDGeNZ), aiming to identify presymptomatic biomarkers. To date, 25 participants, including six confirmed mutation carriers and 19 non-carriers, have undergone baseline clinical, biochemical, and imaging assessments.

Biological Effects

Splicing 
This intronic mutation resides on an intronic splicing silencer and destabilizes a stem-loop structure formed at the exon 10 / intron 10 junction that normally blocks access of U1 snRNA to the 5′ splice site. This increased accessibility causes more frequent inclusion of exon 10 and an increased proportion of the four-repeat (4R) tau isoforms (Hutton et al., 1998; Goedert et al., 1999; Grover et al., 1999; Jiang et al., 2000; de Silva et al., 2006; Lisowiec et al., 2015), which is more prone to aggregation (Esteras et al., 2017).

As noted above, tau inclusions in IVS10+16 C>T carriers are composed mainly of 4R2N tau (Pickering-Brown et al., 2002) and increased 4R tau has been observed in the cerebrospinal fluid of symptomatic carriers (Horie et al., 2022). In addition, neurons derived from induced pluripotent stem cells (iPSCs) and microRNA-induced neurons expressing the mutation showed elevated 4R tau expression compared to control cells (Verheyen et al., 2018; Capano et al., 2022; Mautone et al., 2025), as did iPSC-derived astrocytes (Setó-Salvia et al., 2022; Ezerskiy et al., 2022) and microglia-like cells (Iyer et al., 2025). As suggested by a study of iPSC-derived cortical neurons, the mutation appears to alter the developmental pattern of tau splicing enabling exon 10 inclusion even in immature neurons which normally express only the 0N3R isoform (Sposito et al., 2015).

Tau aggregation, mislocalization, and hyperphosphorylation
The IVS10+16 C>T mutation contributes to tau pathology through aggregation, mislocalization, and hyperphosphorylation. iPSC-derived retinal neural cultures expressing the mutation displayed toxic tau aggregates, detected with the TTCM2 antibody, and tau oligomers, detected with the TOMA2 antibody (Mautone et al., 2025). Similarly, microRNA-induced neurons derived from mutation carriers exhibited tau seeds and increased oligomeric and conformationally abnormal tau, as detected by TOC1 and MC1 antibodies, which was not observed in healthy and isogenic controls (Capano et al., 2022). In contrast, mutant iPSC-derived neurons in other studies lacked insoluble tau (Verheyen et al., 2018; Paonessa et al., 2019), likely due to differences in neuronal induction methods, with microRNA-based reprogramming producing a more adult-like neuronal phenotype.

Tau localization within cells has also been found to be disrupted. Tau is normally localized to axons, which was the case for control iPSC-derived neurons, but neurons derived from patients carrying the IVS10+16 C>T mutation frequently expressed tau in the cell bodies and dendrites instead (Paonessa et al., 2019).

Increased tau phosphorylation is a prominent feature of the IVS10+16 C>T mutation. In mutated iPSC-derived neurons, including retinal cells, hyperphosphorylation was observed at multiple sites compared to controls, including Ser202/Thr205 (AT8), Thr231, Thr212/Ser214, Ser262, Ser396/Ser404 (PHF1), and Thr181 (AT270; Mautone et al., 2025; Paonessa et al., 2019; Verheyen et al., 2018). Similarly, microRNA-induced neurons derived from fibroblasts of IVS10+16 C>T carriers expressed increased phosphorylation compared to healthy control cells at Ser202/Thr205 (AT8), S202 (CP13), and Ser396/Ser404 (PHF1; Capano et al., 2022). Consistent with these findings, postmortem brain tissue from individuals with FTD with the IVS10+16 C>T mutation exhibited increased AT8 immunostaining compared to healthy controls (Dando et al., 2024).

Microtubule abnormalities
The IVS10+16 C>T mutation disrupts microtubule dynamics and cytoskeletal integrity in neuronal models. Live imaging of iPSC-derived excitatory cortical neurons from patients with the mutation revealed that total microtubule movements did not differ from control neurons (Jan 2019 news, Paonessa et al., 2019). However, in mutant neurons, microtubules tended to invade the nucleus, which rarely occurred in control cells. This aberrant invasion caused deformation of the nuclear envelope and defective nucleocytoplasmic transport. Consistent with these functional defects, the study also reported increased invaginations of the nuclear lamina in postmortem brain tissue (frontal and temporal cortex) of FTD patients with the IVS10+16 C>T mutation.

Further evidence of microtubule dysfunction was observed in iPSC-derived retinal neurons expressing the IVS10+16 C>T mutation, studied in 2D cultures and 3D organoids (Mautone et al., 2025). In both systems, cell differentiation and maturation were stunted based on developmental markers and optic vesicle formation. Additionally, cytoskeletal proteins, including those associated with microtubule stability and maturation, were expressed at lower levels compared to controls, highlighting compromised cytoskeletal integrity.

Transcriptional abnormalities
Significant transcriptomic changes have been observed in IVS10+16 C>T iPSC-derived neurons, involving neurodevelopmental pathways. Analysis of iPSC-derived cortical neurons engineered to express the IVS10+16 C>T mutation, for example, revealed impaired WNT/SHH signaling and reduced neural progenitor proliferation potential (Verheyen et al., 2018). Additionally, these IVS10+16 C>T neurons exhibited altered subtype profiles compared with control neurons, with increased expression of limbic, GABAergic, and basal ganglia cell markers and decreased forebrain and glutamatergic markers. These transcriptomic shifts were recapitulated in iPSCs derived from an individual with the IVS10+16 C>T mutation.

Further studies have elucidated the breadth of gene dysregulation. RNA sequencing of iPSC-derived neurons from individuals carrying the IVS10+16 C>T mutation identified 1,804 differentially regulated genes compared to isogenic controls (Minaya et al., 2023). This study also evaluated cells carrying two other MAPT mutations and identified 11 commonly affected genes between the three mutation groups, which were related to synaptic signaling, neuronal projection pathways, lysosomal function, and calcium homeostasis. Notably, 973 differentially expressed genes overlapped with those in neurons carrying another exon 10 mutation (P301L), and many differentially expressed genes were also found in brain samples from patients with tauopathy carrying the same IVS10+16 C>T mutation.

The same research group also examined long non-coding RNA (lncRNA) expression levels in iPSC-derived IVS10+16 C>T neurons (Sep 2023 news, Bhagat et al., 2023). Compared to CRISPR/Cas9-generated isogenic control cells, mutant cells exhibited differential expression of 766 lncRNAs, 15 of which overlapped with other MAPT-mutated iPSC-derived neurons, indicating a common molecular signature. Among these, expression of SNHG8—which is involved in stress granule formation—was identified as a lncRNA of interest and also found to be reduced in the brain of a patient with tauopathy who carried the IVS10+16 C>T mutation. Building on these lncRNA findings, a more recent study investigated small regulatory non-coding RNAs, specifically microRNAs, in iPSC-derived neurons carrying the IVS10+16 C>T mutation (Manzini et al., 2025). Compared to isogenic wild-type neurons, miR-320a, miR-320b, and miR-92a-3p were significantly upregulated, suggesting that these microRNAs, alongside lncRNAs, may contribute to aberrant gene expression patterns in those with the IVS10+16 C>T mutation.

Neuronal dysfunction
Beyond the broad transcriptomic changes observed in IVS10+16 C>T mutation carriers, altered expression of specific genes and proteins critical for synaptic function further highlights the neuropathology associated with this mutation. In an RNA sequencing experiment of postmortem brain tissue (superior temporal gyrus and primary visual cortex) from patients with FTD carrying the IVS10+16 C>T mutation, over 2,000 genes were differentially expressed compared to control individuals without neurological disease (Dando et al., 2024). Specifically, genes involved in synaptic transmission, plasticity, and assembly as well as in NMDA receptor activity and learning were downregulated, while those involved in transcriptional regulation, DNA damage response, and neuroinflammation were upregulated. Immunohistochemistry also revealed reduced presynaptic synaptophysin, pointing to synaptic defects at the protein level. Similarly, iPSC-derived retinal neurons had reduced expression of presynaptic proteins (i.e., VGluT1 and syngirin1), although not of postsynaptic proteins (i.e., PSD-95, Homer-1, and GluR-2; Mautone et al., 2025). Moreover, iPSC-derived cortical organoids from IVS10+16 C>T carriers showed delayed cortical differentiation and synaptic maturation (including synaptic gene expression; Cordella et al., 2024 preprint). 

These transcriptional alterations are paralleled by electrophysiological abnormalities. For instance, iPSC-derived neurons from patients with FTD carrying the IVS10+16 C>T mutation displayed a depolarized resting membrane potential, which was due to decreased Nav1.6 expression, leading to impaired action potential firing (Kopach et al., 2020). Comparable findings in iPSC-derived cortical neurons engineered to express the IVS10+16 C>T mutation showed a depolarized resting membrane potential and reduced Nav1.6 protein level, as well as reduced currents from voltage-gated Na+- and K+-channels and increased input resistance (Kopach et al., 2021). A subsequent report by the same research group found that IVS10+16 C>T iPSC-derived neurons had impaired glutamatergic signaling, with pathological activity patterns observed in electrophysiological experiments (Esteras et al., 2022). These neuronal activity disturbances were accompanied by increased surface expression of AMPA and NMDA receptor subunits and altered glutamate-induced calcium responses, as detected through pharmacological and electrophysiological approaches. Additional experiments pointed to an increase in reactive oxygen species possibly mediating these changes. 

Non-cell–autonomous effects from astrocytes seem to contribute to some  alterations in neuronal excitability and signaling. One study of IVS10+16 C>T–expressing iPSC-derived astrocytes found these cells were unable to take up glutamate from the media, and when they were cocultured with iPSC-derived neurons, spontaneous neuronal activity was increased compared to that observed in cocultures with isogenic control astrocytes (Ezerskiy et al., 2022). 

These excitability changes are accompanied by disruptions in calcium homeostasis. Spontaneous calcium transients in iPSC-derived retinal neural cultures were weaker in both “fast cells” (presumed neurons) and “slow cells” (presumed glia or differentiating retinal cells), suggesting defects in network functionality associated with the IVS10+16 C>T mutation (Mautone et al., 2025). In another report of IVS10+16 C>T iPSC-derived cortical neurons, reduced calcium levels were found under basal conditions, as well as following release of intracellular calcium stores. This was accompanied by changes in the expression of genes related to calcium regulation (Minaya et al., 2023).

However, effects distinct from those described above have also been reported. For example, one study found spontaneous calcium oscillations in mutant iPSC-derived cortical neurons (Britti et al., 2020). In another study, mutant iPSC-derived cortical neurons showed no differences in early neuronal differentiation or electrophysiologically assessed synaptic function compared to controls (Biswas et al., 2016). The contrasting findings may stem from differences in the cell type examined—retinal versus cortical neurons, for example—as well as other experimental design differences, such as length of iPSC differentiation protocols.

Additional alterations in neuronal physiology include observations of increased expression and activity of matrix metalloproteinase-9 and -2, proteolytic enzymes known to regulate differentiation (Biswas et al., 2016). These increases were also found to underlie an elevated rate of cell death. Consistent with this finding, iPSC-derived retinal neurons exhibited greater levels of apoptosis markers, including cleaved caspase-3 and nuclear p53 expression (Mautone et al., 2025). In addition, these cells exhibited increased markers of autophagic stress, as detected by an increase in p62/SQSTM1 puncta and greater formation of stress granules.

Neuroinflammation
The IVS10+16 C>T mutation also appears to contribute to neuroinflammatory processes. In postmortem brain tissue from individuals with FTD carrying the IVS10+16 C>T mutation, decreased levels of GFAP (astrocyte marker) and P2Y12 (microglia marker) were observed by immunostaining and gene expression compared to healthy controls, suggesting that glial activity may be impacted (Dando et al., 2024). In addition, another study showed cellular abnormalities in iPSC-derived IVS10+16 C>T astrocytes—mutant cells were more vulnerable to oxidative stress and displayed higher levels of expression of pan-reactive (e.g., Vimentin and SERPINA3) and neurotoxic (e.g., C3 and SERPING1) genes (Ezerskiy et al., 2022).

Microglial dysfunction has also been investigated in the context of the IVS10+16 C>T mutation. As reported in a preprint, microglia isolated from postmortem brain tissue as well as iPSC-derived microglia-like cells (iMGLs) from individuals carrying the IVS10+16 C>T mutation have multiple molecular and cellular defects (Jun 2024 news, Iyer et al., 2025). Using RNA sequencing of iMGLs, the authors found that the IVS10+16 C>T mutation alters microglial transcriptional states, with significant upregulation of chemokine genes and up- and downregulation of genes involved in phagocytosis, disease-associated microglia (DAM), and lipid-associated microglia (LAM), indicating a likely shift in microglial function. Notably, there was a substantial overlap (n=100 genes) between these dysregulated genes in iMGLs and those in the middle temporal gyrus from patients with FTLD harboring the IVS10+16 C>T mutation.

Cytoskeletal abnormalities were also observed in these IVS10+16 C>T iMGLs compared to isogenic control cells—namely, α-tubulin was redistributed to the cell periphery and F-actin levels were reduced (Jun 2024 news, Iyer et al., 2025). Moreover, live-cell imaging demonstrated impaired phagocytosis of myelin and tau preformed fibrils. Alterations in the expression of genes in the TREM2/TYROBP cell signaling pathway may potentially underlie these changes, as well as others, including endolysosomal function and metabolism.

The secretome from these IVS10+16 C>T iMGLs was also altered compared to isogenic controls (Jun 2024 news, Iyer et al., 2025). Indeed, when iPSC-derived neurons derived from healthy individuals were exposed to media from IVS10+16 C>T iMGLs, the neurons showed reduced synaptic density and increased dendritic length. Together, these findings highlight that the IVS10+16 C>T mutation drives cell-autonomous microglial dysfunction and can also exert non-cell–autonomous pathogenic effects on neurons.

Mitochondrial defects
The IVS10+16 C>T mutation disrupts mitochondrial function across various cellular models. In iPSC-derived retinal neurons, Mitotracker imaging revealed fewer mitochondria with size distribution skewed toward smaller mitochondria compared to isogenic controls, which may suggest cellular stress or impaired maturation (Mautone et al., 2025). Similarly, in IVS10+16 C>T–expressing cortical organoids, there were fewer mitochondria and they were smaller in size; mitochondrial function also appeared to be disrupted based on gene expression changes, as reported in a preprint (Cordella et al., 2024).

Other studies have demonstrated functional mitochondrial impairments as a result of the IVS10+16 C>T mutation. Mitochondrial membranes were hyperpolarized in iPSC-derived neurons from patients with FTD carrying the IVS10+16 C>T mutation (Esteras et al., 2017), and mitochondrial membrane polarization was also found to correlate with levels of 4R isoform expression in these cells (Starkie et al., 2024). Furthermore, mitochondrial membrane hyperpolarization in mutant cells was associated with an overproduction of reactive oxygen species in mitochondria and oxidative stress as detected by increased lipid peroxidation, together leading to increased cell death (Esteras et al., 2017). Additional effects of the IVS10+16 C>T mutation on mitochondria in this study included lower NADH levels, reduced complex I–mediated respiration, and a shift from oxidative phosphorylation to glycolysis for ATP production. In a separate report, iPSC-derived cortical neurons from individuals with the IVS10+16 C>T mutation were found to be more vulnerable to apoptosis in response to mitochondrial calcium overload (Britti et al., 2020).

This variant’s PHRED-scaled CADD score, which integrates diverse information in silico, was 17.05, below the commonly used threshold of 20 for predicting deleteriousness (CADD v1.7, Apr 2024).

Pathogenicity

Frontotemporal Dementia Spectrum : Pathogenic*

*Clinical phenotypes varied 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.

Research Models

The IVS10+16 C>T mutation has been extensively studied using various in vivo and cellular research models to elucidate its role in human disease. An early transgenic mouse model carrying a human transgene with this intronic mutation recapitulates disease-related phenotypes, including abnormal tau phosphorylation, synapse loss and dysfunction, memory impairment, glial activation, tangle formation, and age-dependent neuronal loss. The model, called Tau609, also has an imbalance of 3R and 4R tau isoforms (higher 4R), confirming in vitro work implicating this intronic mutation in the misregulation of exon 10 splicing (Umeda et al., 2013). In a more recently developed mouse model called MAPT 10IVS+16 C>T, an endogenous mouse Mapt-containing region is replaced with the entire human MAPT gene including regulatory non-coding sequences (Benzow et al., 2024).  

Human cellular models have further expanded research capabilities. A resource of human fibroblasts, iPSCs, and neural progenitor cells expressing the IVS10+16 C>T mutation is available (Karch et al., 2019; Oct 2019 news). Numerous other iPSC-derived lines—mainly neurons—have been used to investigate the impact of this intronic mutation on cell function (e.g., Mautone et al., 2025; Setó-Salvia et al., 2022; Ezerskiy et al., 2022; Verheyen et al., 2018; Paonessa et al., 2019). In addition, a triple-mutant iPSC model (García-León et al., 2018), iPSC-derived astrocytes (Ezerskiy et al., 2022), and iPSC-derived microglia-like cells (Jun 2024 news, Iyer et al., 2025) have been generated. In addition to 2D cell cultures, mutant–expressing organoids have been developed from human pluripotent stem cells (e.g., Bertucci et al., 2023; Cordella et al., 2024 preprint).

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References

Research Models Citations

1. Tau609 (Tau 10 + 16)
2. MAPT 10IVS+16 C>T

News Citations

1. Introducing: iPSC Collection from Tauopathy Patients 23 Oct 2019
2. Microglia Make Tau, Spelling Their Demise in Tauopathies 7 Jun 2024
3. Invasion of the Microtubules: Mutant Tau Deforms Neuronal Nuclei 19 Jan 2019
4. Missing ‘Lnc’? Long Noncoding RNAs Bind Tau, Tame Stress Granules 22 Sep 2023

Mutations Citations

1. MAPT R406W
2. MAPT P301L

Paper Citations

1. Umeda T, Yamashita T, Kimura T, Ohnishi K, Takuma H, Ozeki T, Takashima A, Tomiyama T, Mori H. Neurodegenerative disorder FTDP-17-related tau intron 10 +16C → T mutation increases tau exon 10 splicing and causes tauopathy in transgenic mice. Am J Pathol. 2013 Jul;183(1):211-25. Epub 2013 May 13 PubMed.
2. Benzow K, Karanjeet K, Oblak AL, Carter GW, Sasner M, Koob MD. Gene replacement-Alzheimer's disease (GR-AD): Modeling the genetics of human dementias in mice. Alzheimers Dement. 2024 Apr;20(4):3080-3087. Epub 2024 Feb 11 PubMed.
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4. Mautone L, Cordella F, Soloperto A, Ghirga S, Di Gennaro G, Gigante Y, Di Angelantonio S. Understanding retinal tau pathology through functional 2D and 3D iPSC-derived in vitro retinal models. Acta Neuropathol Commun. 2025 Jan 29;13(1):19. PubMed.
5. Setó-Salvia N, Esteras N, de Silva R, de Pablo-Fernandez E, Arber C, Toomey CE, Polke JM, Morris HR, Rohrer JD, Abramov AY, Patani R, Wray S, Warner TT. Elevated 4R-tau in astrocytes from asymptomatic carriers of the MAPT 10+16 intronic mutation. J Cell Mol Med. 2022 Feb;26(4):1327-1331. Epub 2021 Dec 24 PubMed.
6. Ezerskiy LA, Schoch KM, Sato C, Beltcheva M, Horie K, Rigo F, Martynowicz R, Karch CM, Bateman RJ, Miller TM. Astrocytic 4R tau expression drives astrocyte reactivity and dysfunction. JCI Insight. 2022 Jan 11;7(1) PubMed.
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