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

Farrah El-Saafin, Cynthia Curry, Tao Ye, Jean Marie Garnier, Isabelle Kolb-Cheynel, Matthieu Stierle, Natalie L. Downer, Mathew P. Dixon, Luc Negroni, Imre Berger, Tim Thomas, Anne K. Voss, William Dobyns, Didier Devys, Laszlo Tora

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


The human general transcription factor TFIID is composed of the TATA-binding protein (TBP) and 13 TBP-associated factors (TAFs). In eukaryotic cells, TFIID is thought to nucleate RNA polymerase II (Pol II) preinitiation complex formation on all protein coding gene promoters and thus, be crucial for Pol II transcription. In a child with intellectual disability, mild microcephaly, corpus callosum agenesis and poor growth, we identified a homozygous splice-site mutation in TAF8 (NM_138572.2: c.781-1G > A). Our data indicate that the patient's mutation generates a frame shift and an unstable TAF8 mutant protein with an unrelated C-terminus. The mutant TAF8 protein could not be detected in extracts from the patient's fibroblasts, indicating a loss of TAF8 function and that the mutation is most likely causative. Moreover, our immunoprecipitation and proteomic analyses show that in patient cells only partial TAF complexes exist and that the formation of the canonical TFIID is impaired. In contrast, loss of TAF8 in mouse embryonic stem cells and blastocysts leads to cell death and to a global decrease in Pol II transcription. Astonishingly however, in human TAF8 patient cells, we could not detect any cellular phenotype, significant changes in genome-wide Pol II occupancy and pre-mRNA transcription. Thus, the disorganization of the essential holo-TFIID complex did not affect global Pol II transcription in the patient's fibroblasts. Our observations further suggest that partial TAF complexes, and/or an altered TFIID containing a mutated TAF8, could support human development and thus, the absence of holo-TFIID is less deleterious for transcription than originally predicted.

Original languageEnglish (US)
Pages (from-to)2171-2186
Number of pages16
JournalHuman molecular genetics
Issue number12
StatePublished - Jun 15 2018
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by funds from Agence Nationale de la Recherche (ANR-13-BSV8–0021-03 DiscoverIID to LT and IB) and the European Research Council Advanced grant (ERC-2013– 340551, Birtoaction to L.T.). This work was also supported by funds from CNRS, INSERM, Strasbourg University and Investissements d’Avenir grants (ANR-10-IDEX-0002–02 and ANR-10-LABX-0030-INRT) to D.D. and L.T., by the Australian National Health and Medical Research Council (NHMRC) though grants and research fellowships (575512, 1003435, 1084504, 1081421) and the Independent Research Institutes Infrastructure Support (IRIIS) Scheme and by the Victorian State Government OIS (Operational Infrastructure Support) grant to A.K.V. and T.T. I.B. is recipient of a senior investigator award from the Wellcome Trust (106115/Z/14/Z). Funding to pay the Open Access publication charges for this article was provided by the European Research Council Advanced grant (ERC-2013-340551, Birtoaction) to L.T.

Fingerprint Dive into the research topics of 'Homozygous TAF8 mutation in a patient with intellectual disability results in undetectable TAF8 protein, but preserved RNA polymerase II transcription'. Together they form a unique fingerprint.

Cite this