Overview

Pathogenicity: Other Tauopathy : Pathogenic
Clinical Phenotype: Tauopathy with Parkinsonism and Motor Neuron Disease
Reference Assembly: GRCh37/hg19
Position: Chr17:44091643 A>T
dbSNP ID: rs63750092
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: AAG to ATG
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 11

Findings

The K317M mutation was identified in two genetically related families from Basque, Spain. The 13 affected individuals in these families presented with symptoms such as dysarthria (difficulty speaking), tremor, and other motor features such as parkinsonism, pyramidalism, and amyotrophy (progressive, painful muscle wasting). The mean age at onset was 48 years and the mean disease duration was six years. In these families the mutation is associated with FTDP-17 and causes a tauopathy with parkinsonism, motor neuron disease, and frontotemporal degeneration (Zarranz et al., 2005).

Neuropathology

Autopsy showed severe degeneration of the substantia nigra with extensive neuronal loss and gliosis. No Lewy bodies or Pick’s bodies were observed. Particularly severe neuron loss was noted in the motor bulbar nuclei and in the anterior horn of the spinal cord. Frequent, diverse inclusions were present in oligodendrocytes and astrocytes, and neurons contained phospho-tau-positive pre-tangles and tangles (Zarranz et al., 2005). Moreover, altered expression of AQ4, GLUC-t, and GLT-1 suggested primary astrogliopathy and oligodendrogliopathy (Ferrer et al., 2020).

Biological Effect

Homogenates from the frontal cortex of mice expressing this variant resulted in seeding and spreading of phosphorylated, non-oligomeric, and non-truncated 4Rtau and 3Rtau in a time- and region-dependent manner when injected into the brains of wildtype mice (Ferrer et al., 2020). Also of note, an in vitro study found that the acetylation of lysines, including K317, accelerated aggregation in 3R tau (Oct 2023 news, Chabkraborty et al., 2023). 

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References

News Citations

1. Acetylation Accelerates Aggregation of 3R, but Not 4R, Tau 6 Oct 2023

Paper Citations

1. Zarranz JJ, Ferrer I, Lezcano E, Forcadas MI, Eizaguirre B, Atarés B, Puig B, Gómez-Esteban JC, Fernández-Maiztegui C, Rouco I, Pérez-Concha T, Fernández M, Rodríguez O, Rodríguez-Martínez AB, de Pancorbo MM, Pastor P, Pérez-Tur J. A novel mutation (K317M) in the MAPT gene causes FTDP and motor neuron disease. Neurology. 2005 May 10;64(9):1578-85. PubMed.
2. Ferrer I, Andrés-Benito P, Zelaya MV, Aguirre ME, Carmona M, Ausín K, Lachén-Montes M, Fernández-Irigoyen J, Santamaría E, Del Rio JA. Familial globular glial tauopathy linked to MAPT mutations: molecular neuropathology and seeding capacity of a prototypical mixed neuronal and glial tauopathy. Acta Neuropathol. 2020 Apr;139(4):735-771. Epub 2020 Jan 6 PubMed.
3. Chakraborty P, Rivière G, Hebestreit A, de Opakua AI, Vorberg IM, Andreas LB, Zweckstetter M. Acetylation discriminates disease-specific tau deposition. Nat Commun. 2023 Sep 22;14(1):5919. PubMed.

Further Reading

No Available Further Reading