Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura

Gallia G. Levy, William C. Nichols, Eric C. Lian, Tatiana Foroud, Jeanette N. McClintick, Beth M. McGee, Angela Y. Yang, David R. Siemieniak, Kenneth R. Stark, Ralph Gruppo, Ravindra Sarode, Susan B. Shurin, Visalam Chandrasekaran, Sally P. Stabler, Hernan Sabio, Eric E. Bouhassira, Jefferson D. Upshaw, David Ginsburg and Han-Mou Tsai
Additional contact information
Gallia G. Levy: Howard Hughes Medical Institute, and Cellular and Molecular Biology Program, University of Michigan Medical Center
William C. Nichols: Children's Hospital Medical Center
Eric C. Lian: Hemophilia and Thrombosis Center and Sylvester Cancer Center, University of Miami and Veterans Affairs Medical Center
Tatiana Foroud: Indiana University School of Medicine
Jeanette N. McClintick: Indiana University School of Medicine
Beth M. McGee: Howard Hughes Medical Institute, and Cellular and Molecular Biology Program, University of Michigan Medical Center
Angela Y. Yang: Howard Hughes Medical Institute, and Cellular and Molecular Biology Program, University of Michigan Medical Center
David R. Siemieniak: Howard Hughes Medical Institute, and Cellular and Molecular Biology Program, University of Michigan Medical Center
Kenneth R. Stark: Howard Hughes Medical Institute, and Cellular and Molecular Biology Program, University of Michigan Medical Center
Ralph Gruppo: Children's Hospital Medical Center
Ravindra Sarode: Blood Bank, University of Texas Southwestern School of Medicine
Susan B. Shurin: Rainbow Babies and Children's Hospital, and the Case Western Reserve University School of Medicine
Visalam Chandrasekaran: Blood Bank, Long Island Jewish Medical Center, and Albert Einstein College of Medicine
Sally P. Stabler: University of Colorado Health Sciences Center
Hernan Sabio: Pediatric Hematology/Oncology, Medical College of Georgia
Eric E. Bouhassira: Albert Einstein College of Medicine
Jefferson D. Upshaw: The Memphis Cancer Center
David Ginsburg: Howard Hughes Medical Institute, and Cellular and Molecular Biology Program, University of Michigan Medical Center
Han-Mou Tsai: Montefiore Medical Center, and Albert Einstein College of Medicine

Nature, 2001, vol. 413, issue 6855, 488-494

Abstract: Abstract Thrombotic thrombocytopenic purpura (TTP) is a life-threatening systemic illness of abrupt onset and unknown cause. Proteolysis of the blood-clotting protein von Willebrand factor (VWF) observed in normal plasma is decreased in TTP patients. However, the identity of the responsible protease and its role in the pathophysiology of TTP remain unknown. We performed genome-wide linkage analysis in four pedigrees of humans with congenital TTP and mapped the responsible genetic locus to chromosome 9q34. A predicted gene in the identifed interval corresponds to a segment of a much larger transcript, identifying a new member of the ADAMTS family of zinc metalloproteinase genes (ADAMTS13). Analysis of patients' genomic DNA identified 12 mutations in the ADAMTS13 gene, accounting for 14 of the 15 disease alleles studied. We show that deficiency of ADAMTS13 is the molecular mechanism responsible for TTP, and suggest that physiologic proteolysis of VWF and/or other ADAMTS13 substrates is required for normal vascular homeostasis.

Date: 2001
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DOI: 10.1038/35097008

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