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Molecular and Cellular Biology, January 2004, p. 96-104, Vol. 24, No. 1
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.1.96-104.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Essential Role for ADAM19 in Cardiovascular Morphogenesis

Hong-Ming Zhou,1 Gisela Weskamp,1 Valérie Chesneau,1 Umut Sahin,1,2 Andrea Vortkamp,3 Keisuke Horiuchi,1 Riccardo Chiusaroli,4 Rebecca Hahn,5 David Wilkes,5 Peter Fisher,6 Roland Baron,4 Katia Manova,7 Craig T. Basson,5 Barbara Hempstead,8 and Carl P. Blobel1*

Cell Biology Program, Sloan-Kettering Institute,1 Molecular Cytology Core Facility, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center,7 Molecular Cardiology Laboratory, Cardiology Division, Department of Cell and Developmental Biology,5 Hematology Division, Department of Medicine, Weill Medical College of Cornell University, New York, New York 10021,8 Department of Molecular and Cellular Biology and Biochemistry, Brown University, Providence, Rhode Island 02912,2 Max Planck Institute for Molecular Genetics, Otto Warburg Laboratory, D14195 Berlin, Germany,3 Department of Orthopaedics and Cell Biology, Yale University School of Medicine, New Haven, Connecticut 06510,4 Department of Anatomy and Cell Biology, Columbia University, New York, New York 100326

Received 18 July 2003/ Returned for modification 16 September 2003/ Accepted 8 October 2003

Congenital heart disease is the most common form of human birth defects, yet much remains to be learned about its underlying causes. Here we report that mice lacking functional ADAM19 (mnemonic for a disintegrin and metalloprotease 19) exhibit severe defects in cardiac morphogenesis, including a ventricular septal defect (VSD), abnormal formation of the aortic and pulmonic valves, leading to valvular stenosis, and abnormalities of the cardiac vasculature. During mouse development, ADAM19 is highly expressed in the conotruncus and the endocardial cushion, structures that give rise to the affected heart valves and the membranous ventricular septum. ADAM19 is also highly expressed in osteoblast-like cells in the bone, yet it does not appear to be essential for bone growth and skeletal development. Most adam19-/- animals die perinatally, likely as a result of their cardiac defects. These findings raise the possibility that mutations in ADAM19 may contribute to human congenital heart valve and septal defects.

* Corresponding author. Mailing address: Cell Biology Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, Box 368, 1275 York Ave., New York, NY 10021. Phone: (212) 639-2915. Fax: (212) 717-3047. E-mail: c-blobel{at}ski.mskcc.org.

Molecular and Cellular Biology, January 2004, p. 96-104, Vol. 24, No. 1
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.1.96-104.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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