Dysregulation of cotranscriptional alternative splicing underlies CHARGE syndrome.

Proc Natl Acad Sci U S A 2018 01 8;115(4):E620-E629. Epub 2018 Jan 8.

Molecular Genetics of Development Laboratory, Department of Biological Sciences, University of Quebec at Montreal, Montreal, QC H2X 3Y7, Canada;

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.

Download full-text PDF

Source
http://www.pnas.org/lookup/doi/10.1073/pnas.1715378115
Publisher Site
http://dx.doi.org/10.1073/pnas.1715378115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5789929PMC
January 2018
9 Reads
9.809 Impact Factor

Publication Analysis

Top Keywords

charge syndrome
12
mutation-negative cases
12
cotranscriptional alternative
12
alternative splicing
12
dysregulation cotranscriptional
8
generated insertional
4
syndrome generated
4
cases charge
4
characterization mouse
4
model mutation-negative
4
mouse model
4
mutagenesis family
4
172 member
4
member fam172a
4
similarity 172
4
sequence similarity
4
report characterization
4
family sequence
4
insertional mutagenesis
4
underlying charge
4

Similar Publications