Mutations

MAPT K317N

Overview

Pathogenicity: Globular Glial Tauopathy : Pathogenic
Clinical Phenotype: Globular Glial Tauopathy
Reference Assembly: GRCh37/hg19
Position: Chr17:44091644 G>C
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: AAG to AAC
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 11

Findings

This mutation was detected in woman with a constellation of symptoms suggestive of frontotemporal dementia, progressive supranuclear palsy, and motor neuron disease (Tacik et al., 2015). Her disease was categorized as globular glial tauopathy (GGT), a rare four-repeat tauopathy characterized by tau inclusions in astrocytes and oligodendrocytes (Ahmed et al., 2011).

Clinically her disease started at the age of 64 with increasing speech difficulties, especially in producing the correct sounds, consistent with primary progressive apraxia of speech. Over a five-year disease duration, she developed cognitive impairment and parkinsonism symptoms, including postural instability, bradykinesia, and limb apraxia, as well as symptoms suggestive of PSP, including vertical gaze palsy. She also had signs of lower motor neuron disease, including muscle fasiculations. Her disease was classified as subtype III of globular glial tauopathy, which is associated with features of both FTD and motor neuron disease.

The mutation carrier had a family history of dementia. Her mother and maternal aunt were clinically diagnosed with Alzheimer’s dementia. They died at the ages of 63 and 70 years, respectively. It is not known if they carried the K317N mutation.

Neuropathology

Autopsy showed lobar atrophy, especially in the inferior frontal gyrus, but also in premotor and motor cortices. White-matter pathology was observed, including vacuoles, gliosis, and loss of myelinated fibers. Extensive tau pathology was present, with tau-positive inclusions in neurons, astrocytes, and oligodendrocytes. The neuronal inclusions resembled pretangles with a limited number of neurofibrillary tangles, predominantly in the anteromedial temporal lobe (Braak stage III). The lesions in astrocytes were described as Gallyas silver–positive granular or globular inclusions. In the white matter there were many globular oligodendroglial inclusions and coiled bodies. The distribution of tau pathology was consistent with a diagnosis of GGT subtype III.

Neither amyloid plaques nor Lewy bodies were observed. The substantia nigra was depigmented with neuronal tau inclusions. There was mild pathology in the corticospinal tract.

Biological Effect

Recombinant tau with the K317N mutation exhibited impaired tubulin polymerization. In addition, the mutation affected tau aggregation in an isoform-specific manner. The mutation accelerated tau filament assembly in 4R tau while decreasing tau aggregation, misfolding, and filament assembly in 3R tau.

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References

Paper Citations

  1. . A novel tau mutation, p.K317N, causes globular glial tauopathy. Acta Neuropathol. 2015 Aug;130(2):199-214. Epub 2015 Apr 22 PubMed.
  2. . Globular glial tauopathies (GGT) presenting with motor neuron disease or frontotemporal dementia: an emerging group of 4-repeat tauopathies. Acta Neuropathol. 2011 Oct;122(4):415-28. PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . A novel tau mutation, p.K317N, causes globular glial tauopathy. Acta Neuropathol. 2015 Aug;130(2):199-214. Epub 2015 Apr 22 PubMed.

Other mutations at this position

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