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Partial deletion of the MAPT gene: a novel mechanism of FTDP-17

Anne Rovelet-Lecrux1, Magalie Lecourtois, Catherine Thomas-Anterion

  • 1Inserm U614, Faculty of medicine, 76183, Rouen, France.

Human Mutation
|March 6, 2009
PubMed

Insights

A genetic deletion in the MAPT gene caused frontotemporal dementia (FTD) by creating a truncated tau protein. This altered tau protein disrupts microtubule binding and dynamics, leading to disease.

Area of Science:

  • Neuroscience
  • Genetics
  • Cell Biology

Background:

  • Frontotemporal dementia (FTD) is a neurodegenerative disorder often associated with tau pathology.
  • The microtubule-associated protein tau (MAPT) gene plays a critical role in microtubule stability.

Observation:

  • A patient with FTD presented with a heterozygous genomic deletion in the MAPT gene, specifically removing exons 6 to 9.
  • This deletion predicts the production of a truncated tau protein lacking its first microtubule-binding domain.

Findings:

  • Cell culture experiments revealed that the truncated tau isoforms exhibited significantly reduced binding to microtubules.
  • Concurrently, these truncated tau isoforms gained the ability to bind microtubule-associated protein-1B (MAP-1B).

Implications:

  • The observed tauopathy likely results from a dual mechanism: loss of normal tau function and a gain of toxic function.
  • The truncated tau may sequester other MAPs, impairing microtubule dynamics and contributing to FTD pathogenesis.

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