Closing the tau loop: the missing tau mutation.

Area of Science:

• Neurogenetics
• Molecular Biology
• Neuropathology

Background:

• Frontotemporal lobar degeneration (FTLD) encompasses a spectrum of neurodegenerative disorders.
• Mutations in the MAPT gene have been linked to FTD, particularly those affecting tau splicing.
• Previous research identified 11 MAPT splice site mutations, with one specific site remaining elusive.

Observation:

• A family presented with autosomal dominant early amnesia, behavioral changes, and parkinsonism.
• Clinical, neuropsychological, and neuroimaging studies were conducted on affected and unaffected family members.
• Sequencing revealed a novel c.915+15A>C mutation in the MAPT gene's exon 10/intron 10 splice junction in all affected individuals.

Findings:

• The identified c.915+15A>C mutation significantly shifted tau splicing towards a predominant exon 10+ pattern.
• This splicing alteration results in an imbalance between 4-repeat and 3-repeat tau isoforms.
• The study confirms this mutation as the cause of FTD in the studied family, linking it to chromosome 17.

Implications:

• This discovery 'closes the tau loop' by identifying the final predicted splice site mutation in the MAPT gene.
• MAPT gene screening is recommended for families with early amnesia, atypical parkinsonism, and behavioral disturbances.
• Understanding tau splicing alterations provides crucial insights into FTD mechanisms and potential therapeutic targets.