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Proc Natl Acad Sci U S A. 2018 Jan 23;115(4):E620-E629. doi: 10.1073/pnas.1715378115. Epub 2018 Jan 8.

Dysregulation of cotranscriptional alternative splicing underlies CHARGE syndrome.

Author information

1
Molecular Genetics of Development Laboratory, Department of Biological Sciences, University of Quebec at Montreal, Montreal, QC H2X 3Y7, Canada.
2
BioMed Research Center, University of Quebec at Montreal, Montreal, QC H2X 3Y7, Canada.
3
Department of Pediatrics, University of Montreal, Montreal, QC H3T 1C5, Canada.
4
Centre Hospitalier Universitaire Sainte-Justine Research Centre, University of Montreal, Montreal, QC H3T 1C5, Canada.
5
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030.
6
Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI 48109.
7
Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109.
8
Department of Neuroscience, University of Michigan Medical School, Ann Arbor, MI 48109.
9
Department of Veterinary Biomedicine, Faculty of Veterinary Medicine, University of Montreal, Montreal, QC J2S 2M2, Canada.
10
Molecular Genetics of Development Laboratory, Department of Biological Sciences, University of Quebec at Montreal, Montreal, QC H2X 3Y7, Canada; pilon.nicolas@uqam.ca.

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 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.

KEYWORDS:

CHARGE syndrome; Fam172a; alternative splicing; neural crest cells; sex reversal

PMID:
29311329
PMCID:
PMC5789929
DOI:
10.1073/pnas.1715378115
[Indexed for MEDLINE]
Free PMC Article

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