MAPT V363I variation in a sporadic case of frontotemporal dementia: variable penetrant mutation or rare polymorphism?

Area of Science:

• Neurogenetics
• Neurodegenerative Diseases

Background:

• The V363I mutation in the microtubule-associated protein tau gene is linked to primary progressive nonfluent aphasia with variable penetrance.
• Frontotemporal dementia (FTD) is a group of progressive neurodegenerative disorders.

Observation:

• The V363I tau gene variation was identified in a patient with sporadic early-onset frontotemporal dementia and in family members.
• The V363I variation was associated with FTD only in the proband.

Findings:

• The proband was homozygous for the progranulin single-nucleotide polymorphism rs9897526 (A allele) and methionine at codon 129 of the prion protein gene.
• The V363I tau variation's pathogenicity is unclear, potentially acting as an incomplete penetrant mutation or rare polymorphism.
• Genetic modifier factors may contribute to the observed pathogenic effects in the patient.

Implications:

• This case challenges the definition of sporadic neurodegenerative diseases, suggesting potential underlying genetic mutations.
• Understanding genetic modifiers is crucial for unraveling the complexity of neurodegenerative diseases like FTD.
• Further research is needed to clarify the V363I variation's role and the influence of genetic modifiers in FTD pathogenesis.