Overview

Pathogenicity: Frontotemporal Dementia : Pathogenic
Clinical Phenotype: Frontotemporal Dementia
Position: (GRCh38/hg38):Chr17:46010324 T>G
Position: (GRCh37/hg19):Chr17:44087690 T>G
dbSNP ID: rs63750756
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Splicing Alteration
Expected Protein Consequence: Isoform Shift; Missense
Codon Change: AAT to AAG
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 10
Research Models: 1

Findings

Among MAPT mutations, the N279K is one of the most frequent causes of familial frontotemporal dementia. The mutation has been identified in at least seven families worldwide. Phenotypic presentation varies, but generally affected individuals develop symptoms of dementia, parkinsonism, and progressive supranuclear palsy. Individuals with the N279K mutation typically have a parkinsonism-predominant phenotype, consistent with the pallido-ponto-nigral degeneration (PPND) subtype of FTD. Personality changes, behavioral changes, and dementia also occur, but they are generally less prominent and/or seen later in the course of the disease (Tsuboi et al., 2002).

One large N279K kindred involving more than 32 affected people across eight generations developed a particularly aggressive form of disease characterized by progressive parkinsonism with dystonia, dementia, ocular motility abnormalities, pyramidal tract dysfunction, frontal lobe release signs, perseverative vocalizations, and urinary incontinence. In this family, symptom onset and death consistently occurred in the fifth decade (Wszolek et al., 1992).

The N279K mutation also has been identified in at least three Japanese families with clinical syndromes resembling progressive supranuclear palsy (PSP) (Ogaki et al., 2011; Ogaki et al., 2012). In the largest of these families, family B, the reported pedigree indicates nine individuals over three generations affected by parkinsonism (n=7) or dementia with parkinsonism (n=2). The N279K mutation appeared to segregate with disease in this family; it was present in three affected carriers (two with parkinsonism with dementia, one with parkinsonism without dementia) and absent in an unaffected relative. Onset in this family ranged from 42 to 46 years of age, with parkinsonism as the initial symptom in all three cases. Symptoms included bradykinesia, rigidity, postural tremors, gaze palsy, and motor impairments.

In another Japanese family, family D, two sisters were affected by PSP, with onset at 42 and 43 years of age, respectively. In both cases, parkinsonism was the initial symptom and they exhibited supranuclear gaze palsy, bradykinesia, rigidity, postural instability, and visual grasping (a fixed gaze on a random object in the environment). The sisters died at age 54 and 51, respectively (Ogaki et al., 2011; Ogaki et al., 2012).

Another Japanese woman, not known to be genealogically connected to the previously described families, developed PSP symptoms at the age of 41 and died 10 years later. She presented first with parkinsonism, and like the two sisters described above, developed supranuclear gaze palsy, bradykinesia, rigidity, postural instability, and visual grasping (Ogaki et al., 2011; Ogaki et al., 2012).

The N279K mutation was also identified in a large Chinese family with autosomal-dominant parkinsonism (Yang et al., 2015). The reported pedigree shows 21 affected family members over four generations. Prior to the identification of their mutation, affected family members were misdiagnosed with Parkinson’s disease due to their prominent parkinsonian symptoms (e.g., rigidity, hypokinesia, postural instability, and tremor). The diagnosis was later corrected to FTD with parkinsonian features. Disease in this family developed early (onset ranged from 39 to 48 years of age), and progressed rapidly (duration varied from four to 11 years). In addition to parkinsonism, personality changes were prominent early in the disease, including apathy, irritability, and disinhibition, and worsened as the disease progressed. Some family members were affected by supranuclear palsy, and dementia was common, although cognitive decline occurred subsequent to parkinsonism. Thirty-nine family members were genotyped (five affected, 34 unaffected) and the N279K mutation segregated completely with the presence of disease.

Neuropathology

Autopsy findings revealed severe neuronal loss with gliosis in the substantia nigra, pontine tegmentum, and globus pallidus, with some loss also in the caudate and putamen. Notably absent were plaques, tangles, Lewy bodies, and amyloid bodies (Wszolek et al., 1992). Although tau tangles are not typical, other types of tau inclusions have been described in neurons and glia in a variety of brain regions, including the cortex, basal ganglia, brain-stem nuclei, and white matter. Inclusions consisted primarily of four-repeat (4R), not three-repeat (3R), isoforms of tau, consistent with PSP (Delisle et al., 1999; Ogaki et al., 2012). In some cases, substantial tau deposition was also observed in the medial temporal cortices and upper and lower motor neurons with accompanying corticospinal tract degeneration (Arima et al., 2000).

Biological Effect

Similar to many intronic mutations in MAPT, the N279K mutation affects exon 10 splicing in vitro, resulting in more frequent incorporation of exon 10 into transcripts and the relative over-production of tau isoforms with four microtubule-binding repeat domains (4R tau) (Delisle et al., 1999). Induced pluripotent stem cells (iPSCs) have been generated from fibroblasts of affected N279K carriers. iPSC-derived neuronal stem cells carrying the N279K mutation also produce more 4R tau than 3R tau. In addition, the neuronal cells show signs of cellular stress, including the accumulation of stress granules and vesicle trafficking deficits (Wren et al., 2015).

This mutation also appears to disrupt tau turnover. In silico analyses predicted it diminishes cathepsin cleavage which was confirmed using in vitro protease assays (Sampognaro et al., 2023). Consistent with these findings, the lysosomal degradation of mutant tau in neuronal-like SH-SY5Y cells, as well as in neurons derived from IPSCs, was reduced.

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References

Paper Citations

1. Tsuboi Y, Uitti RJ, Delisle MB, Ferreira JJ, Brefel-Courbon C, Rascol O, Ghetti B, Murrell JR, Hutton M, Baker M, Wszolek ZK. Clinical features and disease haplotypes of individuals with the N279K tau gene mutation: a comparison of the pallidopontonigral degeneration kindred and a French family. Arch Neurol. 2002 Jun;59(6):943-50. PubMed.
2. Wszolek ZK, Pfeiffer RF, Bhatt MH, Schelper RL, Cordes M, Snow BJ, Rodnitzky RL, Wolters EC, Arwert F, Calne DB. Rapidly progressive autosomal dominant parkinsonism and dementia with pallido-ponto-nigral degeneration. Ann Neurol. 1992 Sep;32(3):312-20. PubMed.
3. Ogaki K, Motoi Y, Li Y, Tomiyama H, Shimizu N, Takanashi M, Nakanishi A, Yokoyama K, Hattori N. Visual grasping in frontotemporal dementia and parkinsonism linked to chromosome 17 (microtubule-associated with protein tau): a comparison of N-Isopropyl-p-[(123)I]-iodoamphetamine brain perfusion single photon emission computed tomography analysis with . Mov Disord. 2011 Feb 15;26(3):561-3. PubMed.
4. Ogaki K, Li Y, Takanashi M, Ishikawa KI, Kobayashi T, Nonaka T, Hasegawa M, Kishi M, Yoshino H, Funayama M, Tsukamoto T, Shioya K, Yokochi M, Imai H, Sasaki R, Kokubo Y, Kuzuhara S, Motoi Y, Tomiyama H, Hattori N. Analyses of the MAPT, PGRN, and C9orf72 mutations in Japanese patients with FTLD, PSP, and CBS. Parkinsonism Relat Disord. 2012 Jul 18; PubMed.
5. Yang Y, Tang BS, Weng L, Li N, Shen L, Wang J, Zuo CT, Yan XX, Xia K, Guo JF. Genetic Identification Is Critical for the Diagnosis of Parkinsonism: A Chinese Pedigree with Early Onset of Parkinsonism. PLoS One. 2015;10(8):e0136245. Epub 2015 Aug 21 PubMed.
6. Delisle MB, Murrell JR, Richardson R, Trofatter JA, Rascol O, Soulages X, Mohr M, Calvas P, Ghetti B. A mutation at codon 279 (N279K) in exon 10 of the Tau gene causes a tauopathy with dementia and supranuclear palsy. Acta Neuropathol. 1999 Jul;98(1):62-77. PubMed.
7. Arima K, Kowalska A, Hasegawa M, Mukoyama M, Watanabe R, Kawai M, Takahashi K, Iwatsubo T, Tabira T, Sunohara N. Two brothers with frontotemporal dementia and parkinsonism with an N279K mutation of the tau gene. Neurology. 2000 May 9;54(9):1787-95. PubMed.
8. Wren MC, Zhao J, Liu CC, Murray ME, Atagi Y, Davis MD, Fu Y, Okano HJ, Ogaki K, Strongosky AJ, Tacik P, Rademakers R, Ross OA, Dickson DW, Wszolek ZK, Kanekiyo T, Bu G. Frontotemporal dementia-associated N279K tau mutant disrupts subcellular vesicle trafficking and induces cellular stress in iPSC-derived neural stem cells. Mol Neurodegener. 2015 Sep 15;10:46. PubMed.
9. Sampognaro PJ, Arya S, Knudsen GM, Gunderson EL, Sandoval-Perez A, Hodul M, Bowles K, Craik CS, Jacobson MP, Kao AW. Mutations in α-synuclein, TDP-43 and tau prolong protein half-life through diminished degradation by lysosomal proteases. Mol Neurodegener. 2023 May 2;18(1):29. PubMed. Correction.

Further Reading

Learn More

1. Japanese Familial Alzheimer's Disease Database