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Transcription and intellectual disability: a mutation resulting in the almost complete loss of a general transcription factor has a much less severe effect than expected

a) schematic representation of the entire TFIID complex b) schematic representation of the partial TFIID complex observed in the patient

Homozygous TAF8 mutation in a patient with intellectual disability results in undetectable TAF8 protein, but preserved RNA polymerase II transcription.

El-Saafin F(1)(2)(3)(4), Curry C(5)(6), Ye T(1)(2)(3)(4), Garnier JM(1)(2)(3)(4), Kolb-Cheynel I(1)(2)(3)(4), Stierle M(1)(2)(3)(4), Downer NL(7), Dixon MP(7), Negroni L(1)(2)(3)(4), Berger I(8), Thomas T(7)(9), Voss AK(7)(9), Dobyns W(10)(11), Devys D(1)(2)(3)(4), Tora L(1)(2)(3)(4).

Hum Mol Genet June 15, 2018

April 13, 2018

The transcription is an essential mechanism for gene expression and is regulated by many protein factors. In humans, the TFIID factor, composed of the TATA box binding protein and 13 associated factors (TAFs: TBP-associated factors), is crucial to the initiation of transcription by RNA polymerase II. In this study, Laszlo Tora’s team at the IGBMC (CNRS, Inserm and University of Strasbourg) associated with American, British and Australian collaborators studied the consequences of a mutation in the gene coding for one of the associated factors, the TAF8 protein, in a child with an intellectual disability. Although this mutation causes an almost complete loss of TAF8, the researchers showed that it did not affect the overall transcription, contrary to what is observed after total inactivation of the TAF8 gene in mice. These results were published on April 13 in the journal Human Molecular Genetics.

The expression of genes coding for proteins requires the assembly of many molecules on a sequence promoting transcription. The first complex to bind to the promoter is the general transcription factor, TFIID, composed of the TATA box binding protein (TBP) and 13 associated factors (TAFs). Current studies suggested that the assembly of an entire TFIID complex was essential for the initiation of transcription and survival of eukaryotic cells.


In a child with an intellectual disability and a major developmental delay, Laszlo Tora’s team showed that a mutation of the TAF8 gene, one of the associated factors, results in a shift in the genetic code reading frame and in the production of an extremely unstable mutant protein, undetectable in cells derived from the patient. In addition, immunoprecipitation and proteomic analyses show that, in these cells, the formation of the TFIID complex is strongly altered and that only partial complexes are identified. Eventually, the researchers showed that this disorganization of the TFIID complex does not affect the overall transcription by RNA polymerase II.


These observations are much unexpected because they contrast with what is observed with complete inactivation of the TAF8 gene in mice. Indeed, the total loss of the TAF8 protein causes extremely early embryonic death and, in mouse embryonic stem cells, an overall decrease in transcription by RNA polymerase II associated with cell death.


The transcription by RNA polymerase II is thus extremely resistant in humans: a small residual quantity of TAF8 proteins is sufficient for the patient's survival. Nevertheless, the alterations of the TFIID complex are probably at the origin of its major developmental delay.


This study was funded by the ANR and the ERC.

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