Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura.
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 identified 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.
Levy
G G
GG
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.
Nichols
W C
WC
Lian
E C
EC
Foroud
T
T
McClintick
J N
JN
McGee
B M
BM
Yang
A Y
AY
Siemieniak
D R
DR
Stark
K R
KR
Gruppo
R
R
Sarode
R
R
Shurin
S B
SB
Chandrasekaran
V
V
Stabler
S P
SP
Sabio
H
H
Bouhassira
E E
EE
Upshaw
J D
JD
Ginsburg
D
D
Tsai
H M
HM
D002874:Chromosome Mapping; D002899:Chromosomes, Human, Pair 9; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D008297:Male; D008666:Metalloendopeptidases / Q000097:blood / Q000235:genetics* / Q000502:physiology; D008969:Molecular Sequence Data; D005810:Multigene Family; D009154:Mutation; D010375:Pedigree; D020161:Physical Chromosome Mapping; D011697:Purpura, Thrombotic Thrombocytopenic / Q000151:congenital / Q000201:enzymology / Q000235:genetics*; D014841:von Willebrand Factor / Q000378:metabolism*
D014841:von Willebrand Factor; D008666:Metalloendopeptidases