Overview

Pathogenicity: Frontotemporal Dementia Spectrum : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP3
Clinical Phenotype Studied: Frontotemporal Dementia, bvFTD, Pick's disease
Position: (GRCh38/hg38):Chr17:45996657 G>T
Position: (GRCh37/hg19):Chr17:44074023 G>T
Transcript: NM_005910; ENST00000351559
dbSNP ID: rs63750376
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GGC to GTC
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 9
Research Models: 2

Findings

This mutation was identified in a large Dutch kindred originally described as having hereditary Pick's disease (see pedigree in Groen and Endtz, 1982). The family, known as HFTD2, had at least 34 affected individuals over seven generations. The mean age of onset was 47 years. Presenting symptoms generally included involved changes in behavior, including disinhibition, aggression, apathy,  depression, and obsessional behavior (Heutink et al., 1997; Rosso et al., 2003; Giannini et al., 2023). Problems with word finding and speech, including mutism, were also reported (van Swieten et al., 1999). Postmortem analysis confirmed the diagnosis of frontotemporal dementia in 15 individuals (Hutton et al., 1998).

A large international retrospective cohort study, conducted through the Frontotemporal Dementia Prevention Initiative and published literature, identified 10 individuals with the G272V mutation in one family (Moore et al., 2020, suppl 1). Most likely, the family is the same one as described above. Of the carriers reported by Moore and colleagues, six were diagnosed with the behavioral variant of FTD and four with dementia not otherwise specified. The mean age of disease onset was 44 years and the mean age at death 55. Of note, this study included both confirmed mutation carriers and family members who were assumed to be carriers based on their clinical phenotype.

This variant was absent from the gnomAD variant database (gnomAD v4.1.0, Apr 2024).

Neuropathology
Multiple cases from the HFTD2 kindred have been examined neuropathologically. Severe frontotemporal lobe atrophy was commonly observed, as well as neuronal loss in the hippocampus and caudate nucleus. "Ballooned cells" were observed in the cortex and basal ganglia, as well as tau-positive inclusions in multiple cortical and subcortical areas (Heutink et al., 1997). A neuropathological study of three cases, aged 54, 56, and 57 at time of death, showed severe loss of neurons and gliosis in the frontal and temporal cortex, and to a lesser extent in the parietal cortex. Neuronal loss was also observed in the hippocampus. The caudate nucleus was degenerated and there was a severe loss of pigmented cells in the substantia nigra. 

Pick bodies  have been observed in several cases (Spillantini et al., 1998; Bronner et al., 2005). In two cases, typical Pick bodies were observed in the dentate gyrus of the hippocampus, and caudate nucleus containing twisted tau filaments with long periodicity consisting only of three-repeat (3R) tau isoforms unphosphorylated at S262 (Bronner et al., 2005).

Insight into the progression of neuropathology was provided by a study that examined post-mortem brain tissues from seven G272V carriers diagnosed with bvFTD who died at different stages of disease (Giannini et al., 2023). The carrier with earliest stage pathology, whose symptoms began at age 39 and who died by euthanasia at age 45, had a high tau burden in the anterior cingulate cortex, subiculum, hippocampal CA1 region, and caudate nucleus. Left-hemisphere regions were generally less affected than right-hemisphere regions. In the carrier with an intermediate stage of disease, the tau burden in gray matter was higher in all the previously mentioned areas, except the anterior cingulate cortex which was similar. In addition, gray matter tau pathology was seen in middle frontal cortex, anterior temporal cortex, dentate gyrus, and inferior parietal lobule. In contrast, gray matter tau pathology was generally reduced in samples of five carriers with late stage disease, likely due to neuronal loss.

White matter pathology was observed in the anterior cingulate cortex, internal capsule, and inferior parietal lobule in the early stage case, expanded to the anterior temporal and transentorhinal cortices in the intermediate stage, and remained relatively stable or increased moderately in the late stage cases (Giannini et al., 2023). 

Early tau pathology was predominantly neuronal, appearing as diffuse neuronal cytoplasmic inclusions, neurofibrillary tangle-like inclusions, neuronal grains, and less often as Pick body-like inclusions, ballooned neurons, and perinuclear rings. Small diffuse threads were seen in white matter with no intracellular oligodendrocytic pathology.

Biological Effect

Microtubule dynamics
G272 is a highly conserved residue within the PGGG motif in the first repeat domain of tau’s microtubule assembly domain (Rizzu et al., 1999). Because the first repeat is present in all tau isoforms, the G272 V substitution is expected to affect all isoforms. 

Most studies indicate G272V reduces tau’s ability to modulate microtubule assembly (reviewed in Strang et al., 2019). For example, in vitro experiments with isolated proteins indicated a 70 percent reduction in the rate of microtubule assembly in 3R tau and a 60 percent reduction in 4R tau (Hasegawa et al., 1998). Moreover, a subsequent in vitro study indicated that G272V increases phosphorylation of serine 202 which inhibits tau’s ability to promote microtubule assembly (Han et al., 2009).

Data from cell-based assays also suggest G272V tau has a reduced ability to interact with microtubules. For example, microinjection of the mutant protein into MCF7 human breast cancer cells (Bunker et al., 2006) or Xenopus oocytes (Delobel et al., 2002) had minimal effects on microtubule dynamics compared to microinjection of wildtype tau.

However, other studies have shown only minor effects of the mutation on microtubule dynamics (Barghorn et al., 2000; Sahara et al., 2000; Combs and Gamblin, 2012). One study found the mutant had no significant effect on either the rate or the maximum level of microtubule polymerization, and actually reduced the lag time for tubulin polymerization (Combs and Gamblin, 2012). Differences in experimental systems may explain some of these discrepancies and reveal different contributing mechanisms. For example, while a study using isolated proteins suggested phosphorylation as key to the mutation’s effect on microtubule assembly (Han et al., 2009), another study, in Xenopus oocytes, found no apparent dependence in the impairment of tau-microtubule interactions on phosphorylation status (Delobel et al., 2002).

Tau aggregation
Most studies indicate G272V increases tau aggregation (reviewed in Strang et al., 2019). In mice overexpressing G272V tau in the brain and spinal cord, for example, tau filaments were observed in neurons and oligodendrocytes (Götz et al., 2001). Both straight and twisted tau filaments with immunoreactivity to AT8 (S202/T205) and AT100 (T212/S214) were observed.

Moreover, in vitro experiments using recombinant 4R mutant proteins indicated G272V increases the rates of filament nucleation and extension (Chang et al., 2008). Biochemical and electron microscopic studies also suggested G272V tau forms filaments at an increased nucleation rate compared to wildtype tau, although the mutant fibrils’ average length was shorter (Combs and Gamblin, 2012).

Of note, G272V does not fuel aggregation in all circumstances. For example, treatment with aggregation-prone wildtype K18 tau fibrils failed to seed aggregation in human embryonic kidney cells expressing G272V tau (Strang et al., 2018). Also, a study using isolated proteins found modest increased aggregation based on ThS fluorescence, but decreased aggregation based on right-angle laser light scattering (Combs and Gamblin, 2012).

Insights into the molecular underpinnings of G272’s effects on aggregation have emerged. An early study using reverse phase high performance liquid chromatography and circular dichroism spectroscopy suggested structural alterations compared to wildtype tau (Jicha et al., 1999), although another study reported no gross structural changes (Barghorn et al., 2000). Subsequently, a study using site-directed spin labeling and electron paramagnetic resonance spectroscopy suggested G272V has a strong impact on fibril structure (Margittai and Langen, 2006). In particular, this study indicated sequence 272-289 forms part of a core of parallel, in-register, β-strands in tau fibrils and G272V facilitates this packaging.

Phosphorylation
Increased levels of phosphorylation in G272V tau compared to wildtype tau have been identified in multiple experimental systems, including tau filaments in mice overexpressing the mutant protein in brain and spinal cord (Götz et al., 2001), the axons of lamprey giant neurons (Lee et al., 2009), and several in vitro assays (e.g., Alonso et al., 2004; Han et al., 2009). Using recombinant proteins in vitro, robust increases in phosphorylation rates were identified at positions T217 and T181 and increased total tau phosphorylation observed at multiple serines and threonines (Alonso et al., 2004).

Specific kinases and phosphatases have been implicated in these changes. For example, G272V tau was reported to promote phosphorylation by cyclin-dependent kinase 5 at S202, S396/404, and S235 (Han et al., 2009) and bind with higher affinity to the SH3 domain of the tyrosine kinase Fyn than wildtype tau (Bhaskar et al., 2005). Other studies have found the mutant protein bound less strongly to protein phosphatase 2A (PP2A; Goedert et al., 2000), and inhibited dephosphorylation by PP2B at S396/404 (Han and Paudel, 2009). However, the balance between phosphorylation and dephosphorylation activities appears to be complex, including not only inhibition, but activation, of dephosphatases. One study found that the G272V mutation promotes tau dephosphorylation by PP2A at S396/404, Ser235, T231, S202/205, and S214, which may help shape the site-specific pattern of G272V phosphorylation (Han and Paudel, 2009).

Changes in phosphorylation may affect G272V’s ability to regulate microtubule dynamics (Han et al., 2009) and contribute to the mutant protein’s mislocalization to dendritic spines (Yu et al., 2024).

Neuronal function
The overexpression of G272V 3R, although not 4R, tau was reported to reduce dendritic spine density and suppress miniature excitatory postsynaptic currents (mEPSCs) in a dynamin-dependent manner in primary rat hippocampal cultures (Yu et al., 2024). Moreover, in lamprey giant neurons, the mutant protein accelerated neuronal degeneration and the swelling of distal dendrites compared to wildtype tau (Lee et al., 2009).

This variant's PHRED-scaled CADD score, which integrates diverse information in silico, was above 20 (32), suggesting a deleterious effect (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.

Research Models

Several mouse models have been generated that carry the G272V mutation together with one or two additional mutations in MAPT to induce pathologies similar to those observed in tauopathies such as FTD and Alzheimer's disease (AD). For example, the THY-Tau22 mouse carries a transgene containing human 4R tau mutated at sites G272V and P301S, that is expressed exclusively in the forebrain and has been used to model AD (Schindowski et al., 2006). The Tg30tau mouse expresses the same mutations in the forebrain and spinal cord (Leroy et al., 2007). In addition, a mouse line carrying three MAPT mutations, G272V, P301L, R406W has been created as a general model of tauopathy (Lim et al., 2001). 

Invertebrate animals, including C. elegans (Lins et al., 2022) and lampreys (Lee et al., 2009), have also been used to create G272V research models. Of note, the C. elegans model, in which the ptl-1 gene was replaced with the orthologous human MAPT gene, revealed no defects in the glutamatergic sensory neurons of either young worms or aged adults (Lins et al., 2022).

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References

Research Models Citations

1. THY-Tau22

Mutations Citations

1. MAPT P301S
2. MAPT P301L
3. MAPT R406W

Paper Citations

1. Schindowski K, Bretteville A, Leroy K, Bégard S, Brion JP, Hamdane M, Buée L. Alzheimer's disease-like tau neuropathology leads to memory deficits and loss of functional synapses in a novel mutated tau transgenic mouse without any motor deficits. Am J Pathol. 2006 Aug;169(2):599-616. PubMed.
2. Leroy K, Bretteville A, Schindowski K, Gilissen E, Authelet M, De Decker R, Yilmaz Z, Buée L, Brion JP. Early axonopathy preceding neurofibrillary tangles in mutant tau transgenic mice. Am J Pathol. 2007 Sep;171(3):976-92. Epub 2007 Aug 9 PubMed.
3. Lim F, Hernández F, Lucas JJ, Gómez-Ramos P, Morán MA, Avila J. FTDP-17 mutations in tau transgenic mice provoke lysosomal abnormalities and Tau filaments in forebrain. Mol Cell Neurosci. 2001 Dec;18(6):702-14. PubMed.
4. Lins J, Hopkins CE, Brock T, Hart AC. The use of CRISPR to generate a whole-gene humanized MAPT and the examination of P301L and G272V clinical variants, along with the creation of deletion null alleles of ptl-1, pgrn-1 and alfa-1 loci. MicroPubl Biol. 2022;2022 Epub 2022 Sep 19 PubMed.
5. Lee S, Jung C, Lee G, Hall GF. Exonic point mutations of human tau enhance its toxicity and cause characteristic changes in neuronal morphology, tau distribution and tau phosphorylation in the lamprey cellular model of tauopathy. J Alzheimers Dis. 2009;16(1):99-111. PubMed.
6. Groen JJ, Endtz LJ. Hereditary Pick's disease: second re-examination of the large family and discussion of other hereditary cases, with particular reference to electroencephalography, a computerized tomography. Brain. 1982 Sep;105 (Pt 3):443-59. PubMed.
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8. Rosso SM, Donker Kaat L, Baks T, Joosse M, de Koning I, Pijnenburg Y, de Jong D, Dooijes D, Kamphorst W, Ravid R, Niermeijer MF, Verheij F, Kremer HP, Scheltens P, van Duijn CM, Heutink P, van Swieten JC. Frontotemporal dementia in The Netherlands: patient characteristics and prevalence estimates from a population-based study. Brain. 2003 Sep;126(Pt 9):2016-22. Epub 2003 Jul 22 PubMed.
9. Giannini LA, Mol MO, Rajicic A, van Buuren R, Sarkar L, Arezoumandan S, Ohm DT, Irwin DJ, Rozemuller AJ, Netherlands Brain Bank, van Swieten JC, Seelaar H. Presymptomatic and early pathological features of MAPT-associated frontotemporal lobar degeneration. Acta Neuropathol Commun. 2023 Aug 2;11(1):126. PubMed.
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12. 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.
13. Spillantini MG, Crowther RA, Kamphorst W, Heutink P, van Swieten JC. Tau pathology in two Dutch families with mutations in the microtubule-binding region of tau. Am J Pathol. 1998 Nov;153(5):1359-63. PubMed.
14. Bronner IF, ter Meulen BC, Azmani A, Severijnen LA, Willemsen R, Kamphorst W, Ravid R, Heutink P, van Swieten JC. Hereditary Pick's disease with the G272V tau mutation shows predominant three-repeat tau pathology. Brain. 2005 Nov;128(Pt 11):2645-53. Epub 2005 Jul 13 PubMed.
15. Rizzu P, Van Swieten JC, Joosse M, Hasegawa M, Stevens M, Tibben A, Niermeijer MF, Hillebrand M, Ravid R, Oostra BA, Goedert M, van Duijn CM, Heutink P. High prevalence of mutations in the microtubule-associated protein tau in a population study of frontotemporal dementia in the Netherlands. Am J Hum Genet. 1999 Feb;64(2):414-21. PubMed.
16. Strang KH, Golde TE, Giasson BI. MAPT mutations, tauopathy, and mechanisms of neurodegeneration. Lab Invest. 2019 Jul;99(7):912-928. Epub 2019 Feb 11 PubMed.
17. Hasegawa M, Smith MJ, Goedert M. Tau proteins with FTDP-17 mutations have a reduced ability to promote microtubule assembly. FEBS Lett. 1998 Oct 23;437(3):207-10. PubMed.
18. Han D, Qureshi HY, Lu Y, Paudel HK. Familial FTDP-17 missense mutations inhibit microtubule assembly-promoting activity of tau by increasing phosphorylation at Ser202 in vitro. J Biol Chem. 2009 May 15;284(20):13422-13433. Epub 2009 Mar 19 PubMed.
19. Bunker JM, Kamath K, Wilson L, Jordan MA, Feinstein SC. FTDP-17 mutations compromise the ability of tau to regulate microtubule dynamics in cells. J Biol Chem. 2006 Apr 28;281(17):11856-63. Epub 2006 Feb 21 PubMed.
20. Delobel P, Flament S, Hamdane M, Jakes R, Rousseau A, Delacourte A, Vilain JP, Goedert M, Buée L. Functional characterization of FTDP-17 tau gene mutations through their effects on Xenopus oocyte maturation. J Biol Chem. 2002 Mar 15;277(11):9199-205. Epub 2001 Dec 26 PubMed.
21. Barghorn S, Zheng-Fischhöfer Q, Ackmann M, Biernat J, von Bergen M, Mandelkow EM, Mandelkow E. Structure, microtubule interactions, and paired helical filament aggregation by tau mutants of frontotemporal dementias. Biochemistry. 2000 Sep 26;39(38):11714-21. PubMed.
22. Sahara N, Tomiyama T, Mori H. Missense point mutations of tau to segregate with FTDP-17 exhibit site-specific effects on microtubule structure in COS cells: a novel action of R406W mutation. J Neurosci Res. 2000 May 1;60(3):380-7. PubMed.
23. 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.
24. Chang E, Kim S, Yin H, Nagaraja HN, Kuret J. Pathogenic missense MAPT mutations differentially modulate tau aggregation propensity at nucleation and extension steps. J Neurochem. 2008 Nov;107(4):1113-23. Epub 2008 Sep 18 PubMed.
25. Strang KH, Croft CL, Sorrentino ZA, Chakrabarty P, Golde TE, Giasson BI. Distinct differences in prion-like seeding and aggregation between Tau protein variants provide mechanistic insights into tauopathies. J Biol Chem. 2018 Feb 16;293(7):2408-2421. Epub 2017 Dec 19 PubMed.
26. Jicha GA, Rockwood JM, Berenfeld B, Hutton M, Davies P. Altered conformation of recombinant frontotemporal dementia-17 mutant tau proteins. Neurosci Lett. 1999 Feb 5;260(3):153-6. PubMed.
27. Margittai M, Langen R. Side chain-dependent stacking modulates tau filament structure. J Biol Chem. 2006 Dec 8;281(49):37820-7. Epub 2006 Oct 5 PubMed.
28. Alonso Ad, Mederlyova A, Novak M, Grundke-Iqbal I, Iqbal K. Promotion of hyperphosphorylation by frontotemporal dementia tau mutations. J Biol Chem. 2004 Aug 13;279(33):34873-81. Epub 2004 Jun 9 PubMed.
29. Bhaskar K, Yen SH, Lee G. Disease-related modifications in tau affect the interaction between Fyn and Tau. J Biol Chem. 2005 Oct 21;280(42):35119-25. Epub 2005 Aug 22 PubMed.
30. Goedert M, Satumtira S, Jakes R, Smith MJ, Kamibayashi C, White CL 3rd, Sontag E. Reduced binding of protein phosphatase 2A to tau protein with frontotemporal dementia and parkinsonism linked to chromosome 17 mutations. J Neurochem. 2000 Nov;75(5):2155-62. PubMed.
31. Han D, Paudel HK. FTDP-17 missense mutations site-specifically inhibit as well as promote dephosphorylation of microtubule-associated protein tau by protein phosphatases of HEK-293 cell extract. Neurochem Int. 2009 Jan;54(1):14-27. Epub 2008 Oct 15 PubMed.
32. Yu K, Yao KR, Aguinaga MA, Choquette JM, Liu C, Wang Y, Liao D. G272V and P301L Mutations Induce Isoform Specific Tau Mislocalization to Dendritic Spines and Synaptic Dysfunctions in Cellular Models of 3R and 4R Tau Frontotemporal Dementia. J Neurosci. 2024 Jul 10;44(28) PubMed.

External Citations

1. Götz et al., 2001

Further Reading