Mutations

MAPT V337M (Seattle Family A)

Overview

Pathogenicity: Frontotemporal Dementia : Pathogenic
Clinical Phenotype: Frontotemporal Dementia
Genomic Mutation Name (MET1): g.132039G>A
Genomic Mutation Name (NT1): g.129219G>A
dbSNP ID: rs63750570
Coding/Non-Coding: Coding
Genomic Region: Exon 12
Mutation Type: Point, Missense
Codon Change: GTG to ATG
Research Models: 3

Findings

Prior to the identification of MAPT as a disease-causing gene, a kindred in Seattle was described with early-onset dementia associated with an autosomal-dominant pattern of inheritance. The initial report described 13 affected family members over three generations with disease onset ranging from 42 to 66 years. Early symptoms included prominent antisocial psychotic or belligerent behavior, leading to an initial diagnosis of paranoid schizophrenia in some cases, although the diagnosis was frequently changed to probable Alzheimer's disease following dementia onset. Autopsy results of affected family members failed to confirm the AD diagnosis and instead led the authors to conclude that the affected family members had a disease of unknown nosologic identity, which they designated “familial presenile dementia with neurofibrillary tangles” (Sumi et al., 1992). This disease was later categorized as FTDP-17, following the discovery of linkage to chromosome 17 (Bird et al., 1997). The genetic linkage was later refined to implicate the gene MAPT (Poorkaj et al., 1998).

Neuropathology

Postmortem analysis revealed neurofibrillary tangles in several regions of the neocortex, amygdala, and parahippocampal gyrus. The neurofibrillary tangles were composed of paired helical filaments. Notably, plaques were absent (Sumi et al., 1992; Spillantini et al., 1996).

Biological Effect

The V337M mutation accelerates aggregation of tau into filaments (Nacharaju et al., 1999). The mutant protein also makes a more favorable substrate for phosphorylation by brain protein kinases than wild-type 4-repeat (4R) tau (Alonso et al., 2004).

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References

Paper Citations

  1. . Familial presenile dementia with psychosis associated with cortical neurofibrillary tangles and degeneration of the amygdala. Neurology. 1992 Jan;42(1):120-7. PubMed.
  2. . Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann Neurol. 1998 Jun;43(6):815-25. PubMed.
  3. . Comparison of the neurofibrillary pathology in Alzheimer's disease and familial presenile dementia with tangles. Acta Neuropathol. 1996 Jul;92(1):42-8. PubMed.
  4. . Accelerated filament formation from tau protein with specific FTDP-17 missense mutations. FEBS Lett. 1999 Mar 26;447(2-3):195-9. PubMed.
  5. . Promotion of hyperphosphorylation by frontotemporal dementia tau mutations. J Biol Chem. 2004 Aug 13;279(33):34873-81. Epub 2004 Jun 9 PubMed.

Further Reading

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Primary Papers

  1. . Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann Neurol. 1998 Jun;43(6):815-25. PubMed.
  2. . Familial presenile dementia with psychosis associated with cortical neurofibrillary tangles and degeneration of the amygdala. Neurology. 1992 Jan;42(1):120-7. PubMed.