Overview

Pathogenicity: Frontotemporal Dementia : Unclear Pathogenicity, Alzheimer's Disease : Unclear Pathogenicity
Clinical Phenotype: Alzheimer's Disease, Frontotemporal Dementia, None, Tauopathy consistent with Pick's Disease
Position: (GRCh38/hg38):Chr17:46010328_46010330 AAG>---
Position: (GRCh37/hg19):Chr17:44087694_44087696 AAG>---
dbSNP ID: rs63750688
Coding/Non-Coding: Coding
DNA Change: Deletion
Expected RNA Consequence: Splicing Alteration
Expected Protein Consequence: Deletion; Isoform Shift
Codon Change: AAG to ---
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 10
Research Models: 2

Findings

This deletion mutation in tau has been found in individuals with frontotemporal dementia and Alzheimer's disease. Currently, it has not been shown to segregate with disease; however, experimental evidence suggests that K280del disrupts normal tau function and strongly promotes aggregation into paired helical filaments, suggesting a pathogenic role.

The K280del mutation was originally identified in a Dutch individual with apparently sporadic FTD; however, segregation with disease could not be determined (Rizzu et al., 1999).

It was later identified in an individual with late-onset Alzheimer’s disease who did not have a family history of AD (Momeni et al., 2009). In this case, the mutation carrier developed dementia at age 71 and died 10 years later. Segregation with disease could not be determined.

Neuropathology

The neuropathology associated with this mutation is variable, consistent with the variable clinical presentation. The individual with FTD was found to have abundant Pick bodies in several brain regions, comprised of 3R but not 4R tau, although 4R tau was detected in the frontal cortex (van Swieten et al., 2007). The patient also had severe atrophy of the frontal and temporal cortices extending into the inferior parietal lobe.

In contrast, the individual with late-onset AD had extensive pathology typical of Alzheimer’s disease, including tangles (Braak stage IV) and neuritic amyloid plaques, and met CERAD criteria for definite AD. Neurofibrillary tangles were abundant in the frontal, parietal, and temporal lobes. No Pick bodies were observed. Lewy body pathology was extensive in the brainstem, midbrain, and limbic regions. There were also signs of vascular dementia, including moderate to severe atherosclerosis in the vessels at the base of the brain. Mild amyloid angiopathy was also noted. In contrast to the individual with FTD, frontotemporal degeneration was not observed (Momeni et al., 2009).

Biological Effect

The K280del mutation is positioned within the second microtubule-binding repeat domain of the tau protein, a domain which is excluded from tau isoforms containing just three repeat regions. The mutation has been shown to affect splicing, inhibiting the inclusion of exon 10 into transcripts and leading to an excess of 3-repeat (3R) transcripts (D’Souza et al., 1999). It also has been shown to reduce the ability of tau to promote microtubule assembly and to strongly promote tau aggregation into paired helical filaments (Rizzu et al., 1999; Barghorn et al., 2000). The pro-aggregation properties of mutant tau protein lead to toxicity in neuroblastoma cells (Khlistunova etal., 2006).

Research Models

A transgenic mouse model expressing a regulatable form of human tau carrying the K280del mutation develops a tauopathy syndrome, characterized by neurofibrillary tangles, gliosis, synapse loss, and neuronal degeneration (Mocanu et al., 2008).

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References

Paper Citations

1. Mocanu MM, Nissen A, Eckermann K, Khlistunova I, Biernat J, Drexler D, Petrova O, Schönig K, Bujard H, Mandelkow E, Zhou L, Rune G, Mandelkow EM. The potential for beta-structure in the repeat domain of tau protein determines aggregation, synaptic decay, neuronal loss, and coassembly with endogenous Tau in inducible mouse models of tauopathy. J Neurosci. 2008 Jan 16;28(3):737-48. PubMed.
2. 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.
3. Momeni P, Pittman A, Lashley T, Vandrovcova J, Malzer E, Luk C, Hulette C, Lees A, Revesz T, Hardy J, de Silva R. Clinical and pathological features of an Alzheimer's disease patient with the MAPT Delta K280 mutation. Neurobiol Aging. 2009 Mar;30(3):388-93. Epub 2007 Aug 27 PubMed.
4. van Swieten JC, Bronner IF, Azmani A, Severijnen LA, Kamphorst W, Ravid R, Rizzu P, Willemsen R, Heutink P. The DeltaK280 mutation in MAP tau favors exon 10 skipping in vivo. J Neuropathol Exp Neurol. 2007 Jan;66(1):17-25. PubMed.
5. D'Souza I, Poorkaj P, Hong M, Nochlin D, Lee VM, Bird TD, Schellenberg GD. Missense and silent tau gene mutations cause frontotemporal dementia with parkinsonism-chromosome 17 type, by affecting multiple alternative RNA splicing regulatory elements. Proc Natl Acad Sci U S A. 1999 May 11;96(10):5598-603. PubMed.
6. 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.
7. Khlistunova I, Biernat J, Wang Y, Pickhardt M, von Bergen M, Gazova Z, Mandelkow E, Mandelkow EM. Inducible expression of Tau repeat domain in cell models of tauopathy: aggregation is toxic to cells but can be reversed by inhibitor drugs. J Biol Chem. 2006 Jan 13;281(2):1205-14. PubMed.

Further Reading

Learn More

1. Alzheimer Disease & Frontotemporal Dementia Mutation Database