Dysregulation of cotranscriptional alternative splicing underlies CHARGE syndrome

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-bind...

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Published in	Proceedings of the National Academy of Sciences - PNAS Vol. 115; no. 4; pp. E620 - E629
Main Authors	Bélanger, Catherine, Bérubé-Simard, Félix-Antoine, Leduc, Elizabeth, Bernas, Guillaume, Campeau, Philippe M., Lalani, Seema R., Martin, Donna M., Bielas, Stephanie, Moccia, Amanda, Srivastava, Anshika, Silversides, David W., Pilon, Nicolas
Format	Journal Article
Language	English
Published	United States National Academy of Sciences 23.01.2018
Series	PNAS Plus
Subjects	Abnormalities Alternative splicing Argonaute 2 protein Biological Sciences CHARGE syndrome Chromatin Defects Deoxyribonucleic acid Developmental disabilities DNA DNA helicase DNA-binding protein Insertional mutagenesis Lesions Mutagenesis Mutation PNAS Plus Rapamycin Rodents Splicing CHARGE syndrome neural crest cells alternative splicing Fam172a sex reversal
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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.
AbstractList	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 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. Significance A timely diagnosis is key for both survival and quality of life of children with CHARGE syndrome (coloboma, heart defects, atresia of choanae, retardation of growth/development, genital abnormalities, and ear anomalies). Such diagnosis is often difficult to establish, in part because many patients test negative for mutation of CHD7 , the only gene associated with this condition to date. Identifying additional CHARGE-associated genes would not only help resolve diagnosis issues but could also help in identifying common pathogenic mechanisms, which in turn could lead to desirable curative interventions for all patients. Here, FAM172A is reported as a new candidate gene for CHARGE syndrome. This discovery has allowed us to reveal a molecular process that is dysregulated in both CHD7 mutation-positive and -negative cases, such defect being correctable in vitro with rapamycin. 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. A timely diagnosis is key for both survival and quality of life of children with CHARGE syndrome (coloboma, heart defects, atresia of choanae, retardation of growth/development, genital abnormalities, and ear anomalies). Such diagnosis is often difficult to establish, in part because many patients test negative for mutation of CHD7 , the only gene associated with this condition to date. Identifying additional CHARGE-associated genes would not only help resolve diagnosis issues but could also help in identifying common pathogenic mechanisms, which in turn could lead to desirable curative interventions for all patients. Here, FAM172A is reported as a new candidate gene for CHARGE syndrome. This discovery has allowed us to reveal a molecular process that is dysregulated in both CHD7 mutation-positive and -negative cases, such defect being correctable in vitro with rapamycin. 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.
Author	Bélanger, Catherine Bérubé-Simard, Félix-Antoine Silversides, David W. Martin, Donna M. Leduc, Elizabeth Bernas, Guillaume Bielas, Stephanie Srivastava, Anshika Pilon, Nicolas Lalani, Seema R. Campeau, Philippe M. Moccia, Amanda
Author_xml	– sequence: 1 givenname: Catherine surname: Bélanger fullname: Bélanger, Catherine organization: Molecular Genetics of Development Laboratory, Department of Biological Sciences, University of Quebec at Montreal, Montreal, QC H2X 3Y7, Canada – sequence: 2 givenname: Félix-Antoine surname: Bérubé-Simard fullname: Bérubé-Simard, Félix-Antoine organization: Molecular Genetics of Development Laboratory, Department of Biological Sciences, University of Quebec at Montreal, Montreal, QC H2X 3Y7, Canada – sequence: 3 givenname: Elizabeth surname: Leduc fullname: Leduc, Elizabeth organization: Molecular Genetics of Development Laboratory, Department of Biological Sciences, University of Quebec at Montreal, Montreal, QC H2X 3Y7, Canada – sequence: 4 givenname: Guillaume surname: Bernas fullname: Bernas, Guillaume organization: Molecular Genetics of Development Laboratory, Department of Biological Sciences, University of Quebec at Montreal, Montreal, QC H2X 3Y7, Canada – sequence: 5 givenname: Philippe M. surname: Campeau fullname: Campeau, Philippe M. organization: Department of Pediatrics, University of Montreal, Montreal, QC H3T 1C5, Canada – sequence: 6 givenname: Seema R. surname: Lalani fullname: Lalani, Seema R. organization: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030 – sequence: 7 givenname: Donna M. surname: Martin fullname: Martin, Donna M. organization: Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI 48109 – sequence: 8 givenname: Stephanie surname: Bielas fullname: Bielas, Stephanie organization: Department of Neuroscience, University of Michigan Medical School, Ann Arbor, MI 48109 – sequence: 9 givenname: Amanda surname: Moccia fullname: Moccia, Amanda organization: Department of Neuroscience, University of Michigan Medical School, Ann Arbor, MI 48109 – sequence: 10 givenname: Anshika surname: Srivastava fullname: Srivastava, Anshika organization: Department of Neuroscience, University of Michigan Medical School, Ann Arbor, MI 48109 – sequence: 11 givenname: David W. surname: Silversides fullname: Silversides, David W. organization: Department of Veterinary Biomedicine, Faculty of Veterinary Medicine, University of Montreal, Montreal, QC J2S 2M2, Canada – sequence: 12 givenname: Nicolas surname: Pilon fullname: Pilon, Nicolas organization: Molecular Genetics of Development Laboratory, Department of Biological Sciences, University of Quebec at Montreal, Montreal, QC H2X 3Y7, Canada
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Keywords	CHARGE syndrome neural crest cells alternative splicing Fam172a sex reversal
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Notes	1C.B. and F.-A.B.-S. contributed equally to this work. Author contributions: N.P. designed research; C.B., F.-A.B.-S., E.L., and G.B. performed research; P.M.C., S.R.L., D.M.M., S.B., A.M., A.S., and D.W.S. contributed new reagents/analytic tools; C.B., F.-A.B.-S., and N.P. analyzed data; and C.B., F.-A.B.-S., and N.P. wrote the paper. Edited by Robb Krumlauf, Stowers Institute for Medical Research, Kansas City, MO, and approved December 11, 2017 (received for review August 31, 2017)
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Snippet	CHARGE syndrome—which stands for coloboma of the eye, heart defects, atresia of choanae, retardation of growth/development, genital abnormalities, and ear... CHARGE syndrome-which stands for coloboma of the eye, heart defects, atresia of choanae, retardation of growth/development, genital abnormalities, and ear... Significance A timely diagnosis is key for both survival and quality of life of children with CHARGE syndrome (coloboma, heart defects, atresia of choanae,... CHARGE syndrome -- which stands for coloboma of the eye, heart defects, atresia of choanae, retardation of growth/development, genital abnormalities, and ear... A timely diagnosis is key for both survival and quality of life of children with CHARGE syndrome (coloboma, heart defects, atresia of choanae, retardation of...
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SubjectTerms	Abnormalities Alternative splicing Argonaute 2 protein Biological Sciences CHARGE syndrome Chromatin Defects Deoxyribonucleic acid Developmental disabilities DNA DNA helicase DNA-binding protein Insertional mutagenesis Lesions Mutagenesis Mutation PNAS Plus Rapamycin Rodents Splicing
Title	Dysregulation of cotranscriptional alternative splicing underlies CHARGE syndrome
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