Journal Article

Dysregulation of cotranscriptional alternative splicing underlies CHARGE syndrome

Bélanger, Catherine, Bérubé-Simard, Félix-Antoine, Silversides, David W., Martin, Donna M., Leduc, Elizabeth, Bernas, Guillaume, Bielas, Stephanie, Srivastava, Anshika, Pilon, Nicolas, Lalani, Seema R., Campeau, Philippe M., Moccia, Amanda

2018

Overview

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.

• Publisher: National Academy of Sciences
• Subject: Abnormalities / Alternative Splicing / Animals / Antibiotics, Antineoplastic - therapeutic use / Argonaute 2 protein / Argonaute Proteins - metabolism / Biological Sciences / Cercopithecus aethiops / CHARGE syndrome / CHARGE Syndrome - etiology / CHARGE Syndrome - metabolism / Chromatin / COS Cells / Defects / Deoxyribonucleic acid / Developmental Biology / Developmental disabilities / Disease Models, Animal / DNA / DNA helicase / DNA-binding protein / DNA-Binding Proteins - genetics / DNA-Binding Proteins - metabolism / Drug Evaluation, Preclinical / Female / Humans / Insertional mutagenesis / Lesions / Male / Mice / Mice, Transgenic / Mutagenesis / Mutation / Neural Crest - embryology / PNAS Plus / Pregnancy / Rabbits / Rapamycin / Rats / Rodents / Sirolimus - therapeutic use / Splicing