Overview

Pathogenicity: Frontotemporal Dementia Spectrum : Likely Pathogenic, Parkinson's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM4, BS2
Clinical Phenotype Studied: Progressive Supranuclear Palsy, bvFTD, Parkinson's Disease, Parkinsonism
Position: (GRCh38/hg38):Chr17:46010374_46010376 AAT>---
Position: (GRCh37/hg19):Chr17:44087740_44087742 AAT>---
Transcript: NM_005910; ENST00000351559
dbSNP ID: rs63751392
Coding/Non-Coding: Coding
DNA Change: Deletion
Expected RNA Consequence: Splicing Alteration
Expected Protein Consequence: Deletion; Isoform Shift
Codon Change: AAT to ---
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 10

Findings

This trinucleotide deletion mutation was first identified in a Spanish family in which individuals across two generations were affected by either Parkinson's disease (PD) or atypical progressive supranuclear palsy (PSP; Pastor et al., 2001). Notably, in addition to several heterozygous carriers, one family member was homozygous for the deletion due to a consanguineous marriage. Due to the limited information available, it is unclear whether the deletion segregates with disease or if the specific genotype (i.e., homozygous vs. heterozygous) affects the clinical phenotype. The reported pedigree shows two brothers affected by PSP; one homozygous for the deletion and one with an unknown genotype. Two uncles were affected by PD at ages 62 and 71; both were heterozygous carriers. Importantly, several heterozygous carriers remained unaffected at advanced ages, including the parents of the two brothers with PSP, who were 79 and 74 years old, and two of their aunts who were 81 and 75 years old, suggesting incomplete penetrance, at least in the heterozygous state.

A second N296del family with a similarly complicated mode of inheritance has been described (Rossi et al., 2004; see also Oliva et al., 2004). The proband was 36 years old when he developed symptoms of a PSP-like syndrome. He developed antecollis (forward flexion of the head and neck), dysarthria (difficulty speaking due to muscular impairment), postural instability with falls, and slowing of ocular movements. Although neither parent was affected, three siblings of the proband's father had significant neurological conditions. A paternal uncle developed atypical parkinsonism at age 51 with resting tremor, rigidity, pyramidal signs, and cognitive impairment. His symptoms were unresponsive to L-dopa and he died nine years after symptom onset. A paternal aunt developed PD at age 63. Her symptoms were responsive to L-dopa. A second paternal uncle reportedly died from ALS. The proband was found to carry a heterozygous deletion, as did the aunt with PD, two asymptomatic sisters of the proband, and three asymptomatic cousins of the proband (the ages of the asymptomatic carriers were not reported). Segregation with disease could not be established and reduced penetrance was suspected.

In an international, retrospective cohort study that collected data from the Frontotemporal Dementia Prevention Initiative and the published literature, four families, including five presumed carriers, were reported (Moore et al., 2020, suppl tables 5-6). Data included both confirmed mutation carriers and family members who were assumed to be carriers based on their clinical phenotype. Mean age at onset was 49.2 years. One of the presumed carriers was diagnosed with the behavioral variant of FTD (bvFTD), two with PSP, and two with PD. The families reported in this study may include the two families described above.

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

Neuropathology

In the Spanish proband, atrophy of the right precentral gyrus and the brainstem were observed, as well as neuron loss and gliosis in the substantia nigra, several brainstem nuclei, and diencephalon. Hyperphosphorylated tau and neurofibrillary tangles were noted in neurons from many brain regions. Accumulated tau was also observed in astrocytes and oligodendrocytes (Ferrer et al., 2003).

Biological Effect

This mutation involves the deletion of three nucleotides, resulting in a predicted protein sequence lacking asparagine (N) at position 296. Reports of biological effects have been mixed. Two in vitro studies using recombinant 4-repeat tau (2N4R and 1N4R) found the mutation robustly reduced the rate and maximum level of microtubule polymerization compared to wildtype tau (Grover et al., 2002; Yoshida et al., 2002). In addition, a higher critical concentration of mutant tau was required to fuel tubulin polymerization (Yoshida et al., 2002). However, another in vitro study, using recombinant 2N4R tau, reported mutant tau had similar effects to wildtype tau on maximum microtubule polymerization, rate of polymerization, and lag time, although a statistically significant alteration in the polymerization rate was reported in a supplementary table (Combs and Gamblin 2012).

Similarly, the reported effects of N296del on tau aggregation have been mixed. Both in a heparin-induced aggregation assay using 1N4R recombinant tau isoforms (Yoshida et al., 2002) and an arachidonic acid-induced assay using 2N4R tau (Combs and Gamblin 2012), mutant tau was found to behave similiarly to wildtype tau. The former study relied on thioflavin T fluorescence, while the latter relied on thioflavin S to measure aggregation. Both studies also used electron microscopy to assess the number and shape of tau filaments. In contrast, Grover and colleagues, using 2N4R tau in heparin-induced assays, reported increased aggregation of mutant tau as assessed by thioflavin S, and observed shorter, more numerous mutant tau filaments compared to those formed by wildtype tau as assesed by electron microscopy (Grover et al., 2002).

Whether N296del affects splicing is also uncertain. While one in vitro study reported that, unlike other mutations affecting codon 296, N296del had little or no effect on splicing (Grover et al., 2002), two other studies found a substantial increase in exon 10 inclusion (Yoshida et al., 2002; Tubeuf et al., 2020).

Also of note, chromosomal aberrations were reported in peripheral blood lymphocytes of several MAPT mutation carriers, including a male carrier of N296del with PSP (Rossi et al., 2013).

Pathogenicity

Frontotemporal Dementia Spectrum : Likely Pathogenic*

*This variant has incomplete penetrance. 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.

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References

Paper Citations

1. Pastor P, Pastor E, Carnero C, Vela R, García T, Amer G, Tolosa E, Oliva R. Familial atypical progressive supranuclear palsy associated with homozigosity for the delN296 mutation in the tau gene. Ann Neurol. 2001 Feb;49(2):263-7. PubMed.
2. Rossi G, Gasparoli E, Pasquali C, Di Fede G, Testa D, Albanese A, Bracco F, Tagliavini F. Progressive supranuclear palsy and Parkinson's disease in a family with a new mutation in the tau gene. Ann Neurol. 2004 Mar;55(3):448. PubMed.
3. Oliva R, Pastor P. Tau gene delN296 mutation, Parkinson's disease, and atypical supranuclear palsy. Ann Neurol. 2004 Mar;55(3):448-9. PubMed.
4. 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.
5. Ferrer I, Pastor P, Rey MJ, Muñoz E, Puig B, Pastor E, Oliva R, Tolosa E. Tau phosphorylation and kinase activation in familial tauopathy linked to deln296 mutation. Neuropathol Appl Neurobiol. 2003 Feb;29(1):23-34. PubMed.
6. Grover A, DeTure M, Yen SH, Hutton M. Effects on splicing and protein function of three mutations in codon N296 of tau in vitro. Neurosci Lett. 2002 Apr 19;323(1):33-6. PubMed.
7. Yoshida H, Crowther RA, Goedert M. Functional effects of tau gene mutations deltaN296 and N296H. J Neurochem. 2002 Feb;80(3):548-51. PubMed.
8. 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.
9. Tubeuf H, Charbonnier C, Soukarieh O, Blavier A, Lefebvre A, Dauchel H, Frebourg T, Gaildrat P, Martins A. Large-scale comparative evaluation of user-friendly tools for predicting variant-induced alterations of splicing regulatory elements. Hum Mutat. 2020 Oct;41(10):1811-1829. Epub 2020 Aug 16 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.

Further Reading