Mutations in TAF8 cause a neurodegenerative disorder

Area of Science:

• Genetics
• Molecular Biology
• Neuroscience

Background:

• Transcription factor II D (TFII D) is crucial for RNA polymerase II transcription initiation.
• TFII D comprises TATA-binding protein and 13 TAF subunits; variants in 5 subunits are linked to human disorders.
• TAF8 is a TAF subunit implicated in TFII D complex assembly and function.

Observation:

• Seven additional patients with TAF8 mutations were identified, including novel splice site mutations and the previously reported c.781-1G>A mutation.
• Mutations led to aberrant splicing, reduced TAF8 expression, and mislocalization.
• Patients presented with severe psychomotor retardation, microcephaly, growth retardation, spasticity, and epilepsy.

Findings:

• Cerebral imaging revealed hypomyelination, thin corpus callosum, and progressive brain atrophy.
• Magnetic resonance spectroscopy showed reduced N-acetylaspartate, indicating neuronal loss.
• TAF8 mutations result in a distinct neurodevelopmental disorder with specific neurological manifestations.

Implications:

• This study confirms TAF8 mutations as a cause of a severe neurodevelopmental disorder.
• The findings highlight the critical role of TAF8 in neuronal development and function.
• The neurological phenotype suggests a specific vulnerability of neuronal tissue to TFII D dysfunction.