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Clinical and Pathological Features of FTDP-17 with MAPT p.K298_H299insQ Mutation

Hiroyuki Morino1,2,3, Takashi Kurashige4, Yukiko Matsuda2

  • 1Department of Medical Genetics, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan.

Movement Disorders Clinical Practice
|April 12, 2024
PubMed
Abstract

Insights

A MAPT gene mutation causes frontotemporal dementia with parkinsonism (FTDP-17), leading to atypical parkinsonism and progressive supranuclear palsy. This study confirms the insACA mutation

Area of Science:

  • Neurogenetics
  • Molecular Biology
  • Neuropathology

Background:

  • The MAPT gene is implicated in frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17).
  • FTDP-17 is a hereditary neurodegenerative disease with diverse clinical presentations including parkinsonism and dementia.
  • Clinical phenotypes can mimic Parkinson's disease, progressive supranuclear palsy, and corticobasal syndrome.

Purpose of the Study:

  • To genetically, biochemically, and pathologically investigate families with MAPT-related disorders.
  • To characterize the impact of a novel MAPT mutation on tau protein function and neuropathology.
  • To correlate genotype with the diverse clinical phenotypes observed in affected individuals.

Main Methods:

  • Genetic analysis: linkage analysis, homozygosity haplotyping, exome sequencing.
  • Biochemical assays: tau protein microtubule polymerization, heparin-induced tau aggregation, western blotting.
  • Pathological examination: immunohistochemistry using anti-tau antibody and PM-PBB3 on autopsy brain tissue.

Main Results:

  • Identified a novel MAPT gene variant (c.896_897insACA, p.K298_H299insQ) in affected individuals.
  • Mutant tau protein exhibited reduced microtubule polymerization and formed abnormal aggregates.
  • Pathology revealed frontotemporal and midbrain atrophy, substantia nigra depigmentation, and tau-positive inclusions characteristic of FTDP-17.

Conclusions:

  • Confirmed the insACA MAPT mutation as a cause of FTDP-17.
  • Clinical progression from parkinsonism to progressive supranuclear palsy symptoms was observed.
  • Further studies on MAPT mutations are needed to elucidate common and specific pathogenic mechanisms.
Keywords:
MAPTParkinson's diseasefrontotemporal dementia with parkinsonism linked to chromosome 17progressive supranuclear palsytau protein

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