TY - JOUR
T1 - Type 2M von Willebrand disease
T2 - F606I and I662F mutations in the glycoprotein Ib binding domain selectively impair ristocetin- but not botrocetin-mediated binding of von Willebrand factor to platelets
AU - Hillery, Cheryl A.
AU - Mancuso, David J.
AU - Sadler, J. Evan
AU - Ponder, Jay W.
AU - Jozwiak, Mary A.
AU - Christopherson, Pamela A.
AU - Gill, Joan Cox
AU - Scott, J. Paul
AU - Montgomery, Robert R.
PY - 1998/3/1
Y1 - 1998/3/1
N2 - von Willebrand disease (vWD) is a common, autosomally inherited, bleeding disorder caused by quantitative and/or qualitative deficiency of von Willebrand factor (vWF). We describe two families with a variant form of vWD where affected members of both families have borderline or low vWF antigen levels, normal vWF multimer patterns, disproportionately low ristocetin cofactor activity, and significant bleeding symptoms. Whereas ristocatin- induced binding of plasma vWF from affected members of both families to fixed platelets was reduced, botrocetin-induced platelet binding was normal. The sequencing of genomic DNA identified unique missense mutations in each family in the vWF axon 28. In Family A, a missense mutation at nucleotide 4105T → A resulted in a Phe606IIe amino acid substitution (F606I) and in Family B, a missense mutation at nucleotide 4273A → T resulted in an IIe662Phe amino acid substitution (I662F). Both mutations are within the large disulfide loop between Cys509 end Cys695 in the A1 domain that mediates vWF interaction with platelet glycoprotein Ib. Expression of recombinant vWF containing either F606I or I662F mutations resulted in mutant recombinant vWF with decreased ristocetin-induced platelet binding, but normal multimer structure, botrocetin-induced platelet binding, collagen binding, and binding to the conformation-sensitive monoclonal antibody, AvW-3. Both mutations are phenotypically distinct from the previously reported valiant type 2M(Milwaukee-1) because of the presence of normal botrocetin-induced platelet binding, collagen binding, and AvW-3 binding, as well as the greater frequency and intensity of clinical bleeding. When the reported type 2M mutations are mapped on the predicted three-dimensional structure of the A1 loop of vWF, the mutations cluster in one region that is distinct from the region in which the type 2B mutations cluster.
AB - von Willebrand disease (vWD) is a common, autosomally inherited, bleeding disorder caused by quantitative and/or qualitative deficiency of von Willebrand factor (vWF). We describe two families with a variant form of vWD where affected members of both families have borderline or low vWF antigen levels, normal vWF multimer patterns, disproportionately low ristocetin cofactor activity, and significant bleeding symptoms. Whereas ristocatin- induced binding of plasma vWF from affected members of both families to fixed platelets was reduced, botrocetin-induced platelet binding was normal. The sequencing of genomic DNA identified unique missense mutations in each family in the vWF axon 28. In Family A, a missense mutation at nucleotide 4105T → A resulted in a Phe606IIe amino acid substitution (F606I) and in Family B, a missense mutation at nucleotide 4273A → T resulted in an IIe662Phe amino acid substitution (I662F). Both mutations are within the large disulfide loop between Cys509 end Cys695 in the A1 domain that mediates vWF interaction with platelet glycoprotein Ib. Expression of recombinant vWF containing either F606I or I662F mutations resulted in mutant recombinant vWF with decreased ristocetin-induced platelet binding, but normal multimer structure, botrocetin-induced platelet binding, collagen binding, and binding to the conformation-sensitive monoclonal antibody, AvW-3. Both mutations are phenotypically distinct from the previously reported valiant type 2M(Milwaukee-1) because of the presence of normal botrocetin-induced platelet binding, collagen binding, and AvW-3 binding, as well as the greater frequency and intensity of clinical bleeding. When the reported type 2M mutations are mapped on the predicted three-dimensional structure of the A1 loop of vWF, the mutations cluster in one region that is distinct from the region in which the type 2B mutations cluster.
UR - http://www.scopus.com/inward/record.url?scp=0032032301&partnerID=8YFLogxK
U2 - 10.1182/blood.v91.5.1572
DO - 10.1182/blood.v91.5.1572
M3 - Article
C2 - 9473222
AN - SCOPUS:0032032301
SN - 0006-4971
VL - 91
SP - 1572
EP - 1581
JO - Blood
JF - Blood
IS - 5
ER -