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Hum Mol Genet. 2018 Jun 15;27(12):2171-2186. doi: 10.1093/hmg/ddy126.

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

El-Saafin F1,2,3,4, Curry C5,6, Ye T1,2,3,4, Garnier JM1,2,3,4, Kolb-Cheynel I1,2,3,4, Stierle M1,2,3,4, Downer NL7, Dixon MP7, Negroni L1,2,3,4, Berger I8, Thomas T7,9, Voss AK7,9, Dobyns W10,11, Devys D1,2,3,4, Tora L1,2,3,4.

Author information

Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch, France.
Centre National de la Recherche Scientifique, UMR7104, 67404 Illkirch, France.
Institut National de la Santé et de la Recherche Médicale, U1258, 67404 Illkirch, France.
Université de Strasbourg, 67404 Illkirch, France.
University of California, San Francisco, San Francisco, CA, USA.
Genetic Medicine, University Pediatric Specialists, Fresno, CA 93701, USA.
Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
School of Biochemistry and Bristol Research Centre for Synthetic Biology BrisSynBio, University of Bristol, Bristol BS8 1TD, UK.
Department of Medical Biology, University of Melbourne, Parkville, VIC 3052, Australia.
Departments of Pediatrics and Neurology, University of Washington, Seattle, WA 98101, USA.
Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA.


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.

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