Human Molecular Genetics Advance Access originally published online on October 12, 2006
Human Molecular Genetics 2006 15(22):3369-3377; doi:10.1093/hmg/ddl413
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Sesn1 is a novel gene for left–right asymmetry and mediating nodal signaling
1 Department of Human Genetics, Clinical Genetics Unit, 2 Department of Developmental Biology, Flanders Interuniversity Institute for Biotechnology and Laboratory of Molecular Biology, 3 Department of Human Genetics, Molecular Genetics Section, Laboratory of Glycobiology and Developmental Genetics, 4 Pediatric Cardiology Unit, University of Leuven, Leuven, Belgium, 5 Université de Liège, Laboratoire de Biologie Moléculaire et Génie Génétique, Institute de Chimie, Liège, Belgium and 6 Baylor College of Medicine, Department of Molecular and Human Genetics, Houston, TX, USA
* To whom correspondence should be addressed at: Department of Human Genetics, Clinical Genetics Unit, University Hospital Leuven, Herestraat 49, B-3000 Leuven, Belgium. Tel: +32 16345903; Fax: +32 16346051; Email: hilde.peeters{at}uz.kuleuven.ac.be
Received May 14, 2006; Accepted October 6, 2006
Remarkable progress has been made in understanding the molecular mechanisms underlying left–right asymmetry in vertebrate animal models but little is known on left–right axis formation in humans. Previously, we identified SESN1 (also known as PA26) as a candidate gene for heterotaxia by positional cloning of the breakpoint regions of a de novo translocation in a heterotaxia patient. In this study, we show by means of a zebrafish sesn1-knockdown model that Sesn1 is required for normal embryonic left–right determination. In this model, developmental defects and expression data of genes implicated in vertebrate left–right asymmetry indicate a role for Sesn1 in mediating Nodal signaling. In the lateral plate mesoderm, Nodal signaling plays a central role in left–right axis formation in vertebrates and is mediated by FoxH1 transcriptional induction. In line with this, we show that Sesn1 physically interacts with FoxH1 or a FoxH1-containing complex. Mutation analysis in a panel of 234 patients with isolated heterotaxia did not reveal mutations, indicating that these are only exceptional causes of human heterotaxia. In this study, we identify SESN1 as an indispensable gene for vertebrate left–right asymmetry and a new player in mediating Nodal signaling.