Molecular Genetics of Development Laboratory, Department of Biological Sciences, University of Quebec at Montreal, Montreal, QC H2X 3Y7, Canada.
BioMed Research Center, University of Quebec at Montreal, Montreal, QC H2X 3Y7, Canada.
Proc Natl Acad Sci U S A. 2018 Jan 23;115(4):E620-E629. doi: 10.1073/pnas.1715378115. Epub 2018 Jan 8.
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 (chromodomain helicase DNA-binding protein 7), known to encode a chromatin remodeler. The genetic lesions responsible for 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 mutation-negative cases of CHARGE syndrome generated by insertional mutagenesis of (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 mutation-positive and mutation-negative cases. We also present evidence that such splicing defects can be corrected in vitro by acute rapamycin treatment.
CHARGE 综合征——代表眼缺陷、心脏缺陷、鼻后孔闭锁、生长/发育迟缓、生殖器官异常和耳部畸形——是一种严重的发育障碍，具有广泛的表型变异性，主要由 （染色质解旋酶 DNA 结合蛋白 7）突变引起，已知该基因编码一种染色质重塑因子。负责 突变阴性病例的遗传病变尚不清楚，至少部分原因是 CHARGE 综合征的致病机制仍未明确。在这里，我们通过插入诱变 （家族与序列相似性 172，成员 A）报告了一种用于 突变阴性 CHARGE 综合征的小鼠模型的特征。我们表明 Fam172a 在共转录性可变剪接的调控中起着关键作用，特别是通过与 Ago2（Argonaute-2）和 Chd7 相互作用。在人类队列中的验证研究使我们能够提出共转录性可变剪接的失调是 突变阳性和 突变阴性病例的统一致病机制。我们还提供了证据表明，这种剪接缺陷可以通过急性雷帕霉素治疗在体外得到纠正。
