Dysregulation of cotranscriptional alternative splicing underlies CHARGE syndrome

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 115; no. 4; pp. E620 - E629
• Main Authors: 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., Pilon, Nicolas
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 23.01.2018
• Series: PNAS Plus
• Subjects: Abnormalities; Alternative splicing; Argonaute 2 protein; Biological Sciences; CHARGE syndrome; Chromatin; Defects; Deoxyribonucleic acid; Developmental disabilities; DNA; DNA helicase; DNA-binding protein; Insertional mutagenesis; Lesions; Mutagenesis; Mutation; PNAS Plus; Rapamycin; Rodents; Splicing; CHARGE syndrome; neural crest cells; alternative splicing; Fam172a; sex reversal
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1715378115

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.