Mutations

MAPT K280del

Overview

Pathogenicity: Frontotemporal Dementia : Unclear Pathogenicity, Alzheimer's Disease : Unclear Pathogenicity
Clinical Phenotype: Alzheimer's Disease, Frontotemporal Dementia, None
Genomic Mutation Name (MET1): g.123729_123731delAAG
Genomic Mutation Name (NT1): g.120908_120910delAAG
dbSNP ID: rs63750688
Coding/Non-Coding: Coding
Genomic Region: Exon 10
Mutation Type: Deletion
Codon Change: AAG to ---

Findings

This mutation is associated with multiple clinical and neuropathological phenotypes; however, it is unclear whether it is truly pathogenic. It was originally identified in a Dutch individual with apparently sporadic frontotemporal dementia, but pathogenicity could not be determined (Rizzu et al., 1999). The mutation was later identified in an individual with late-onset Alzheimer’s disease who did not have a family history of AD. In the latter case, the proband was an 81-year-old man with a 10-year history of dementia prior to death (Momeni et al., 2009).

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 cortex 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 variant is unusal in that it inhibits exon 10 inclusion and leads to an excess of 3-repeat (3R) tau transcripts (D’Souza et al., 1999). It also has been shown to reduce the ability of tau to promote microtubule assembly (Rizzu et al., 1999).

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References

Paper Citations

  1. . 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.
  2. . 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.
  3. . The DeltaK280 mutation in MAP tau favors exon 10 skipping in vivo. J Neuropathol Exp Neurol. 2007 Jan;66(1):17-25. PubMed.
  4. . 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.

Further Reading

Papers

  1. . Frontotemporal dementia in The Netherlands: patient characteristics and prevalence estimates from a population-based study. Brain. 2003 Sep;126(Pt 9):2016-22. Epub 2003 Jul 22 PubMed.
  2. . The heritability and genetics of frontotemporal lobar degeneration. Neurology. 2009 Nov 3;73(18):1451-6. PubMed.

Learn More

Alzheimer Disease & Frontotemporal Dementia Mutation Database

Primary Papers

  1. . 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.
  2. . 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.