Dysregulation of cotranscriptional alternative splicing underlies CHARGE syndrome

Bélanger, Catherine; Bérubé-Simard, Félix-Antoine; Leduc, Elizabeth; Bernas, Guillaume; Campeau, Philippe M.; Lalani, Seema R.; Martin, Donna M.; Bielas, Stephanie; Moccia, Amanda; Srivastava, Anshika; Silversides, David W. et Pilon, Nicolas (2018). « Dysregulation of cotranscriptional alternative splicing underlies CHARGE syndrome ». Proceedings of the National Academy of Sciences, 115(4), E620-E629.

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CHARGE syndrome—which stands for coloboma of the eye, heart defects, atresia of choanae, retardation of growth/development, genital abnormalities, and ear anomalies—is a severe developmental disorder with wide phenotypic variability, caused mainly by mutations in CHD7 (chromodomain helicase DNA-binding protein 7), known to encode a chromatin remodeler. The genetic lesions responsible for CHD7 mutation-negative cases are unknown, at least in part because the pathogenic mechanisms underlying CHARGE syndrome remain poorly defined. Here, we report the characterization of a mouse model for CHD7 mutation-negative cases of CHARGE syndrome generated by insertional mutagenesis of Fam172a (family with sequence similarity 172, member A). We show that Fam172a plays a key role in the regulation of cotranscriptional alternative splicing, notably by interacting with Ago2 (Argonaute-2) and Chd7. Validation studies in a human cohort allow us to propose that dysregulation of cotranscriptional alternative splicing is a unifying pathogenic mechanism for both CHD7 mutation-positive and CHD7 mutation-negative cases. We also present evidence that such splicing defects can be corrected in vitro by acute rapamycin treatment.

Type: Article de revue scientifique
Mots-clés ou Sujets: alternative splicing, CHARGE syndrome, neural crest cells, sex reversal, Fam172a
Unité d'appartenance: Centres institutionnels > Centre de recherches biomédicales (BIOMED)
Faculté des sciences > Département des sciences biologiques
Déposé par: Jean-Jacques Rondeau
Date de dépôt: 18 janv. 2019 11:13
Dernière modification: 18 janv. 2019 11:13
Adresse URL : http://archipel.uqam.ca/id/eprint/12094


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