TAF8 MUTATION CAUSES INTELLECUAL DISABILITY, TFIID DISASSEMBLY WITH NO EFFECT ON RNA POLYMERASE II TRANSCRIPTION

The human general transcription factor TFIID is composed of the TATA-binding protein (TBP) and 13 TBP-associated factors (TAFs). In eukaryotic cells, TFIID nucleates RNA Polymerase II (Pol II) preinitiation complex formation on gene promoters and thus, is crucial for Pol II transcription. Germline knock out of several mouse TFIID subunits (Tbp, Taf7, Taf8, and Taf10) results in lethality at embryonic day 4.0, demonstrating the fundamental role of holo-TFIID in transcription. We identified a child harboring a splice-site mutation in TAF8, who has intellectual disability, poor growth, progressive spasticity and microcephaly. The c.781-G>A TAF8 mutation in this patient resulted in a frame shift, which affected the final 50 carboxy terminal amino acids of TAF8. We found that the mutant TAF8 protein is unstable and the patient c.781-G>A TAF8 primary fibroblasts did not form canonical TFIID complexes. Astonishingly however, genome-wide RNA pol II occupancy and pre-mRNA transcription on the tested genes was unaffected in the patient’s primary fibroblasts. This study indicates that perturbed TFIID function is less deleterious for transcription in human cells than originally anticipated.