Pathogenicity: Frontotemporal Dementia : Pathogenic
Clinical Phenotype: Frontotemporal Dementia
Reference Assembly: GRCh37/hg19
Position: Chr17:44095995 G>A
dbSNP ID: rs63750570
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GTG to ATG
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 12
Research Models: 3


Before MAPT was identified as a disease-causing gene, a kindred in Seattle was described with early onset dementia associated with an autosomal-dominant pattern of inheritance. The initial report described 13 affected family members over three generations with disease onset ranging from 42 to 66 years. Early symptoms included prominent antisocial, psychotic, or belligerent behavior, leading to an initial diagnosis of paranoid schizophrenia in some cases, although the diagnosis was frequently changed to probable Alzheimer's disease following dementia onset. Autopsy results of affected family members failed to confirm the AD diagnosis and instead led the authors to conclude that the affected family members had a disease which they designated “familial presenile dementia with neurofibrillary tangles” (Sumi et al., 1992). This disease was later categorized as FTDP-17, following the discovery of linkage to chromosome 17 (Poorkaj et al., 1997). The genetic linkage was later refined to implicate MAPT (Poorkaj et al., 1998).

More recently,  a U.S family, reported as “family A” was described (Spina et al., 2017). The proband developed compulsions, irritability, and mental inflexibility at age 30. He later developed memory and orientation deficits. He became apathetic and developed paranoid ideations. He had a family history of dementia with behavioral abnormalities. The proband’s maternal great grandparent and maternal grandparent were affected. The proband’s mother became disinhibited in her 40s. She exhibited a slow decline in cognition and became more rigid in her behavior and thinking. She survived until age 82. Her sibling developed personality changes at age 50 and died at age 64. A sibling of the proband also developed personality change in their late 30s. The V337M mutation was identified in the proband and in affected family members.

Another US family has been described, reported as "family B" (Spina et al., 2017). At age 55 the proband became apathetic, irritable, verbally abusive, and emotionally blunted. She became mentally rigid and had difficulty recognizing faces. She suffered marked memory impairment and deficits in executive function. She also developed a postural tremor. She died at age 68. She had a family history of dementia with behavior abnormalities. Her father developed FTD at age 61 and died at age 66 of myocardial infarct. Autopsy confirmed his diagnosis. Her father’s four siblings had similar clinical symptoms with onset in their 40s and 50s. The proband’s sister was diagnosed with schizoaffective disorder in early life but later developed early onset dementia. The V337M mutation was identified in the proband and in affected family members.


Postmortem analysis revealed neurofibrillary tangles in several regions of the neocortex, amygdala, and parahippocampal gyrus. The neurofibrillary tangles were composed of paired helical filaments. Notably, plaques were absent (Sumi et al., 1992; Spillantini et al., 1996).

More recently, autopsy findings from two V337M mutation carriers were reported (Spina et al., 2017). A case from “family A”, showed severe atrophy in the frontal and temporal lobes, along with the CA1 region of the hippocampus and subiculum. The highest density of neurofibrillary tangles and pretangles was in the middle frontal cortex, anterior cingulate gyrus, caudate nucleus, and amygdala. There was mild neuronal loss and gliosis in the substantia nigra. Tufted tau-positive astrocytes were seen in the putamen. TDP-43 pathology was observed in the form of neuronal cytoplasmic inclusions, especially in the CA1 region of the hippocampus, dentate gyrus, subiculum, basal ganglia, and some neocortical areas. There was also neuronal loss and gliosis associated with hippocampal sclerosis. Diffuse Aβ plaques were present in the cortex and neuritic plaques were present in the CA1/subiculum, dentate gyrus, and CA4 region of the hippocampus. Amyloid angiopathy was absent as was α-synuclein pathology. The tau pathology observed in this case matched the topography of the signal in the brain of her living son as measured by PET imaging with the experimental tau tracer [18F]AV1451 (Spina et al., 2017).

The other case, from “family B” showed severe atrophy of the temporal pole, insula, amygdala, orbitofrontal cortex, and ventromedial striatum. Mild neurofibrillary tangle pathology was seen in the entorhinal cortex, CA1/subiculum, and median raphe. Pretangles were abundant in many regions of the cortex including the frontal pole, as well as the amygdala and thalamus, among other areas. All tau inclusions stained with both 3R and 4R tau antibodies. Lewy bodies and Lewy neurites were observed in the cingulate cortex, amygdala, entorhinal cortex, and substantia nigra, among other regions. Amyloid deposits were not observed, nor were TDP-43 deposits (Spina et al., 2017).

Biological Effect

The V337M mutation accelerates aggregation of tau into filaments (Nacharaju et al., 1999). The mutant protein also makes a more favorable substrate for phosphorylation by brain protein kinases than wild-type tau (Alonso et al., 2004). Moreover, V733M tau binds more tightly than wildtype tau to the cytoskeletal protein EB3 causing the axon initial segment to shorten, making neurons hyperexcitable and decreasing plasticity (Sep 2019 news, Sohn et al., 2019).

Last Updated: 06 Sep 2023


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News Citations

  1. Mutant Tau Stiffens Axon Cytoskeleton Near Soma

Paper Citations

  1. . Familial presenile dementia with psychosis associated with cortical neurofibrillary tangles and degeneration of the amygdala. Neurology. 1992 Jan;42(1):120-7. PubMed.
  2. . Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann Neurol. 1998 Jun;43(6):815-25. PubMed.
  3. . Frontotemporal dementia with the V337M MAPT mutation: Tau-PET and pathology correlations. Neurology. 2017 Feb 21;88(8):758-766. Epub 2017 Jan 27 PubMed.
  4. . Comparison of the neurofibrillary pathology in Alzheimer's disease and familial presenile dementia with tangles. Acta Neuropathol. 1996 Jul;92(1):42-8. PubMed.
  5. . Accelerated filament formation from tau protein with specific FTDP-17 missense mutations. FEBS Lett. 1999 Mar 26;447(2-3):195-9. PubMed.
  6. . Promotion of hyperphosphorylation by frontotemporal dementia tau mutations. J Biol Chem. 2004 Aug 13;279(33):34873-81. Epub 2004 Jun 9 PubMed.
  7. . Pathogenic Tau Impairs Axon Initial Segment Plasticity and Excitability Homeostasis. Neuron. 2019 Nov 6;104(3):458-470.e5. Epub 2019 Sep 18 PubMed.

Further Reading


  1. . Chromosome 17 and hereditary dementia: linkage studies in three non-Alzheimer families and kindreds with late-onset FAD. Neurology. 1997 Apr;48(4):949-54. PubMed.

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Protein Diagram

Primary Papers

  1. . Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann Neurol. 1998 Jun;43(6):815-25. PubMed.
  2. . Familial presenile dementia with psychosis associated with cortical neurofibrillary tangles and degeneration of the amygdala. Neurology. 1992 Jan;42(1):120-7. PubMed.


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