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

Date publication

avril 2018

Journal

Human molecular genetics

Auteurs

Membres identifiés du Cancéropôle Est :
Dr DEVYS Didier , Dr TORA Laszlo , Dr NEGRONI Luc , Mme KOLB-CHEYNEL Isabelle

Tous les auteurs :
El-Saafin F, Curry C, Ye T, Garnier JM, Kolb-Cheynel I, Stierle M, Downer NL, Dixon MP, Negroni L, Berger I, Thomas T, Voss AK, Dobyns W, Devys D, Tora L

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/29648665

Résumé

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.

Mots clés

Animals, Blastocyst, metabolism, Cell Death, genetics, Disease Models, Animal, Drosophila, genetics, Homozygote, Humans, Intellectual Disability, diagnostic imaging, Mice, Microcephaly, diagnostic imaging, Mouse Embryonic Stem Cells, metabolism, Mutation, RNA Polymerase II, genetics, Transcription Factor TFIID, genetics, Transcription, Genetic

Référence

Hum. Mol. Genet.. 2018 Apr 10;: