The TBP gene encodes TATA Box-Binding Protein, the DNA-binding subunit of the RNA polymerase II transcription factor D (TFIID). As the name suggests, the TBP subunit attaches to the DNA promoter at its TATA box, to initiate transcription. Binding of the TFIID complex at the promoter helps in positioning of RNA Polymerase II and serves as a scaffold for the assembly of other polypeptides to the transcription complex. It also acts as a channel for regulatory signals.
Mutations in the TBP gene have been associated with Spinocerebellar Ataxia 17 (SCA17), a progressive neurodegenerative disorder characterised by gait and limb ataxia, intention tremors, cerebellar atrophy and behavioural manifestations such as psychosis, disorientation and aggression. The gene has also been associated with an increased susceptibility to Late-Onset Parkinson Disease.
The TBP gene is located on the long arm of chromosome 6 and spans a length of 18.5 kb. Its coding sequence is contained within 8 exons and it encodes a 37.6 kDa protein product composed of 339 amino acids. An additional 35.6 kDa isoform of the protein exists due to an alternatively spliced transcript variant. TBP is ubiquitously expressed in the human body. SCA17 is caused by the heterozygous expansion of the CAG/CAA trinucleotide repeat in the gene increasing it from 25-42 in the wild-type to 43-66 in the mutant protein. The abnormally long resulting TBP protein accumulates in neurons, leading to their dysfunction and eventual death. Recent studies have also found homozygous and compound heterozygous mutations in the TBP gene of SCA17 affected individuals.
Monies et al. (2017) described the genomic landscape of Saudi Arabia based on the findings of 1000 diagnostic panels and exomes. One patient, a 28-year-old female, presented with a familial disease with mental subnormality, walking difficulties and abnormal movement. Whole exome sequencing helped identify a homozygous mutation (c.171delG, p.Q57 fs) in exon 2 of the patient’s TBP gene. As TBP is associated with the autosomal dominant SCA17, this finding presented a unique case of a recessive mutation in a gene normally associated with a dominant phenotype.