Title |
Dysregulation of cotranscriptional alternative splicing underlies CHARGE syndrome
|
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Published in |
Proceedings of the National Academy of Sciences of the United States of America, January 2018
|
DOI | 10.1073/pnas.1715378115 |
Pubmed ID | |
Authors |
Catherine Bélanger, Félix-Antoine Bérubé-Simard, Elizabeth Leduc, Guillaume Bernas, Philippe M. Campeau, Seema R. Lalani, Donna M. Martin, Stephanie Bielas, Amanda Moccia, Anshika Srivastava, David W. Silversides, Nicolas Pilon |
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. |
X Demographics
Geographical breakdown
Country | Count | As % |
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Canada | 2 | 25% |
United States | 2 | 25% |
Unknown | 4 | 50% |
Demographic breakdown
Type | Count | As % |
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Members of the public | 8 | 100% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
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Unknown | 46 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
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Student > Ph. D. Student | 12 | 26% |
Researcher | 8 | 17% |
Student > Doctoral Student | 5 | 11% |
Student > Bachelor | 5 | 11% |
Student > Master | 3 | 7% |
Other | 3 | 7% |
Unknown | 10 | 22% |
Readers by discipline | Count | As % |
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Biochemistry, Genetics and Molecular Biology | 20 | 43% |
Agricultural and Biological Sciences | 6 | 13% |
Medicine and Dentistry | 4 | 9% |
Neuroscience | 3 | 7% |
Nursing and Health Professions | 2 | 4% |
Other | 2 | 4% |
Unknown | 9 | 20% |