A novel MAPT mutation associated with the clinical phenotype of progressive nonfluent aphasia

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Mutations in the microtubule-associated protein tau gene (MAPT) are linked to frontotemporal lobar degeneration (FTLD) with tau pathology.
• These mutations often affect tau's microtubule-binding domains, compromising its ability to interact with microtubules.
• Progressive nonfluent aphasia (PNFA) is a clinical manifestation of FTLD, characterized by language deficits.

Purpose of the Study:

• To identify and characterize a novel MAPT variant in a patient diagnosed with PNFA and a family history of dementia.
• To investigate the potential impact of this variant on tau protein function and its role in neurodegeneration.

Main Methods:

• Clinical assessment and diagnosis of PNFA based on established criteria.
• Neuroimaging (Brain CT) and cerebrospinal fluid analysis.
• Genetic sequencing to identify MAPT variants, including in silico analysis for functional predictions.
• Screening of additional FTLD patients and controls to assess variant frequency.

Main Results:

• A novel MAPT exon 10 variant (g.123798G > A, p.Gly304Ser) was identified in the second microtubule-binding domain.
• In silico analysis predicted the variant to be damaging to tau protein structure and function.
• The variant was absent in 168 FTLD patients and 503 controls, suggesting it is a rare mutation.

Conclusions:

• The identified MAPT variant likely compromises tau's ability to regulate microtubule dynamics.
• This novel variant is a potential cause of PNFA and contributes to the understanding of FTLD pathogenesis.
• Further research is warranted to fully elucidate the functional consequences and clinical implications of this MAPT mutation.