Dysregulation of cotranscriptional alternative splicing underlies CHARGE syndrome.

Abstract

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 <i>CHD7</i> (chromodomain helicase DNA-binding protein 7), known to encode a chromatin remodeler. The genetic lesions responsible for <i>CHD7</i> 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 <i>CHD7</i> mutation-negative cases of CHARGE syndrome generated by insertional mutagenesis of <i>Fam172a</i> (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 <i>CHD7</i> mutation-positive and <i>CHD7</i> mutation-negative cases. We also present evidence that such splicing defects can be corrected in vitro by acute rapamycin treatment.