1. Howard Hughes Medical Institute, Departments of Internal Medicine and Human Genetics, and Cellular and Molecular Biology Program, University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA
2. Division of Human Genetics, Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA
3. Hemophilia and Thrombosis Center and Sylvester Cancer Center, University of Miami and Veterans Affairs Medical Center, Miami, Florida 33136, USA
4. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
5. Division of Hematology/Oncology, Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA
6. Blood Bank, University of Texas Southwestern School of Medicine, Dallas, Texas 75390, USA
7. Department of Pediatrics, Rainbow Babies and Children's Hospital, and the Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA
8. Blood Bank, Long Island Jewish Medical Center, and Albert Einstein College of Medicine, New Hyde Park, New York 11040, USA
9. Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA
10. Pediatric Hematology/Oncology, Medical College of Georgia, Augusta, Georgia 30912, USA
11. Department of Medicine/Hematology and Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA
12. The Memphis Cancer Center, Memphis, Tennessee 38119, USA
13. Division of Hematology, Montefiore Medical Center, and Albert Einstein College of Medicine, Bronx, New York 10467, USA

Correspondence to: David Ginsburg¹ Correspondence and requests for materials should be addressed to D.G. (e-mail: ginsburg@umich.edu). Original cDNA and sequence-tagged site sequences reported here are available from GenBank under accession numbers AF414400, AF414401, G73162, G73163, G73164 and G73165.

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.

1. Howard Hughes Medical Institute, Departments of Internal Medicine and Human Genetics, and Cellular and Molecular Biology Program, University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA
2. Division of Human Genetics, Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA
3. Hemophilia and Thrombosis Center and Sylvester Cancer Center, University of Miami and Veterans Affairs Medical Center, Miami, Florida 33136, USA
4. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
5. Division of Hematology/Oncology, Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA
6. Blood Bank, University of Texas Southwestern School of Medicine, Dallas, Texas 75390, USA
7. Department of Pediatrics, Rainbow Babies and Children's Hospital, and the Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA
8. Blood Bank, Long Island Jewish Medical Center, and Albert Einstein College of Medicine, New Hyde Park, New York 11040, USA
9. Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA
10. Pediatric Hematology/Oncology, Medical College of Georgia, Augusta, Georgia 30912, USA
11. Department of Medicine/Hematology and Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA
12. The Memphis Cancer Center, Memphis, Tennessee 38119, USA
13. Division of Hematology, Montefiore Medical Center, and Albert Einstein College of Medicine, Bronx, New York 10467, USA

Correspondence to: David Ginsburg¹ Correspondence and requests for materials should be addressed to D.G. (e-mail: ginsburg@umich.edu). Original cDNA and sequence-tagged site sequences reported here are available from GenBank under accession numbers AF414400, AF414401, G73162, G73163, G73164 and G73165.