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; Han Mou Tsai

doi:10.1038/35097008

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, Han Mou Tsai

Cell Biology

Research output: Contribution to journal › Review article › peer-review

1507 Scopus citations

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.

Original language	English (US)
Pages (from-to)	488-494
Number of pages	7
Journal	Nature
Volume	413
Issue number	6855
DOIs	https://doi.org/10.1038/35097008
State	Published - Oct 4 2001

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Levy, G. G., Nichols, W. C., Lian, E. C., Foroud, T., McClintick, J. N., McGee, B. M., Yang, A. Y., Siemieniak, D. R., Stark, K. R., Gruppo, R., Sarode, R., Shurin, S. B., Chandrasekaran, V., Stabler, S. P., Sabio, H., Bouhassira, E. E., Upshaw, J. D., Ginsburg, D., & Tsai, H. M. (2001). Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature, 413(6855), 488-494. https://doi.org/10.1038/35097008

Levy, GG, Nichols, WC, Lian, EC, Foroud, T, McClintick, JN, McGee, BM, Yang, AY, Siemieniak, DR, Stark, KR, Gruppo, R, Sarode, R, Shurin, SB, Chandrasekaran, V, Stabler, SP, Sabio, H, Bouhassira, EE, Upshaw, JD, Ginsburg, D & Tsai, HM 2001, 'Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura', Nature, vol. 413, no. 6855, pp. 488-494. https://doi.org/10.1038/35097008

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title = "Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura",

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.",

author = "Levy, {Gallia G.} and Nichols, {William C.} and Lian, {Eric C.} and Tatiana Foroud and McClintick, {Jeanette N.} and McGee, {Beth M.} and Yang, {Angela Y.} and Siemieniak, {David R.} and Stark, {Kenneth R.} and Ralph Gruppo and Ravindra Sarode and Shurin, {Susan B.} and Visalam Chandrasekaran and Stabler, {Sally P.} and Hernan Sabio and Bouhassira, {Eric E.} and Upshaw, {Jefferson D.} and David Ginsburg and Tsai, {Han Mou}",

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AU - Levy, Gallia G.

AU - Nichols, William C.

AU - Lian, Eric C.

AU - Foroud, Tatiana

AU - McClintick, Jeanette N.

AU - McGee, Beth M.

AU - Yang, Angela Y.

AU - Siemieniak, David R.

AU - Stark, Kenneth R.

AU - Gruppo, Ralph

AU - Sarode, Ravindra

AU - Shurin, Susan B.

AU - Chandrasekaran, Visalam

AU - Stabler, Sally P.

AU - Sabio, Hernan

AU - Bouhassira, Eric E.

AU - Upshaw, Jefferson D.

AU - Ginsburg, David

AU - Tsai, Han Mou

PY - 2001/10/4

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N2 - 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.

AB - 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.

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

Abstract

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