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<p>Frontotemporal dementia represents a group of clinical syndromes characterized by progressive changes in behavior or language that are associated with frontotemporal lobe atrophy. Around 40% of FTD cases are familial, with mutations in <i>MAPT</i> representing a major familial form. Among <i>MAPT</i> variants, substitutions at codon 301 – notably P301L, P301S, and P301T – are established pathogenic causes of autosomal-dominant frontotemporal lobar degeneration (FTLD). In contrast, a P301A substitution has not, to our knowledge, been reported in patients. Here, we describe a novel P301A <i>MAPT</i> variant presenting with early onset, rapidly progressive FTLD. We show, using biochemical and cellular assays, that P301A tau fibrillizes faster and seeds more robustly than wild-type and P301L tau, with performance comparable to P301S. These findings suggest the P301A variant is pathogenic. This work expands the <i>MAPT</i> variant spectrum in FTLD, and supports a model in which distinct substitutions at P301 differentially influence tau aggregation and prion-like propagation.</p>

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Early onset rapidly progressive frontotemporal dementia due to a novel MAPT P301A variant with functional validation of pathogenicity

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月25日

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  • Kiet Hua,
  • Maryam R. Pearson,
  • Brandon I. Apresa,
  • Jesseca M. Chung,
  • Andrew J. Ambrose,
  • Susan M. Hiatt,
  • Argentina Lario Lago,
  • Matthew GH Hall,
  • Liya Rabkina,
  • Stephanie Kwan,
  • Joyce Do,
  • Iyas Daghlas,
  • Annie McDonough,
  • Elan L. Guterman,
  • Denise J. Xu,
  • Howard J. Rosen,
  • Jane Grimwood,
  • J. Nicholas Cochran,
  • Michelle R. Arkin,
  • Adam L. Boxer,
  • Jennifer S. Yokoyama,
  • Peter A. Ljubenkov,
  • Brandon B. Holmes

摘要

Frontotemporal dementia represents a group of clinical syndromes characterized by progressive changes in behavior or language that are associated with frontotemporal lobe atrophy. Around 40% of FTD cases are familial, with mutations in MAPT representing a major familial form. Among MAPT variants, substitutions at codon 301 – notably P301L, P301S, and P301T – are established pathogenic causes of autosomal-dominant frontotemporal lobar degeneration (FTLD). In contrast, a P301A substitution has not, to our knowledge, been reported in patients. Here, we describe a novel P301A MAPT variant presenting with early onset, rapidly progressive FTLD. We show, using biochemical and cellular assays, that P301A tau fibrillizes faster and seeds more robustly than wild-type and P301L tau, with performance comparable to P301S. These findings suggest the P301A variant is pathogenic. This work expands the MAPT variant spectrum in FTLD, and supports a model in which distinct substitutions at P301 differentially influence tau aggregation and prion-like propagation.