TY - JOUR
T1 - The p.P1127S pathogenic variant lowers von Willebrand factor levels through higher affinity for the macrophagic scavenger receptor LRP1: Clinical phenotype and pathogenic mechanisms
AU - Sacco, Monica
AU - Lancellotti, Stefano
AU - Branchini, Alessio
AU - Tardugno, Maira
AU - Testa, Maria Francesca
AU - Lunghi, Barbara
AU - Bernardi, Francesco
AU - Pinotti, Mirko
AU - Giusti, Betti
AU - Castaman, Giancarlo
AU - De Cristofaro, Raimondo
PY - 2022
Y1 - 2022
N2 - Background The index case is a 21-year-old Italian woman with a mild hemorrhagic syndrome and von Willebrand factor antigen (VWF:Ag) = 34.3 U/dl, VWF recombinant glycoprotein Ib (VWF:GpIbR) = 32.8 U/dl, and factor VIII (FVIII) = 55.3 IU/dl. Aims The aim of this study is to characterize from a genetic and biochemical standpoint this low VWF phenotype. Methods Coagulation and biochemical methods were used to study the structural and functional pattern of VWF multimers in the index case's plasma. Recombinant wild-type and p.P1127S VWF variants were produced using human embryonic kidney (HEK)-293 cells. In addition, genetic screening was carried out to detect single nucleotide variants of some scavenger VWF/FVIII receptor genes such as CLEC4M, STAB2, and ASGR2. Results Genetic investigation revealed that the index case inherited from her mother the heterozygous missense mutation c.3379C > T (VWF exon 25), causing the p.P1127S substitution in the VWF D ' D3 domain. The index case was also homozygous for the scavenger receptor ASGR2 c.-95 CC-genotype. Desmopressin normalized the VWF level of the patient, although its clearance was faster (t(1/2) = 6.7 h) than in normal subjects (t(1/2) = 12 +/- 0.7 h). FVIII-VWF interaction, A Disintegrin And Metalloprotease with ThromboSpondin type 1 motif-13 levels, ristocetin-induced-platelet-aggregation, and VWF multimeric pattern were normal. The p.P1127S variant was normally synthesized and secreted by HEK-293 cells, and molecular modeling predicts a conformational change showing higher affinity for the macrophagic scavenger receptor lipoprotein receptor-related protein 1 (LRP1), as also experimentally verified. Conclusions The p.P1127S variant may cause a low VWF phenotype, stemming from an increased VWF affinity for the scavenger receptor LRP1 and, consequently, an accelerated clearance of VWF.
AB - Background The index case is a 21-year-old Italian woman with a mild hemorrhagic syndrome and von Willebrand factor antigen (VWF:Ag) = 34.3 U/dl, VWF recombinant glycoprotein Ib (VWF:GpIbR) = 32.8 U/dl, and factor VIII (FVIII) = 55.3 IU/dl. Aims The aim of this study is to characterize from a genetic and biochemical standpoint this low VWF phenotype. Methods Coagulation and biochemical methods were used to study the structural and functional pattern of VWF multimers in the index case's plasma. Recombinant wild-type and p.P1127S VWF variants were produced using human embryonic kidney (HEK)-293 cells. In addition, genetic screening was carried out to detect single nucleotide variants of some scavenger VWF/FVIII receptor genes such as CLEC4M, STAB2, and ASGR2. Results Genetic investigation revealed that the index case inherited from her mother the heterozygous missense mutation c.3379C > T (VWF exon 25), causing the p.P1127S substitution in the VWF D ' D3 domain. The index case was also homozygous for the scavenger receptor ASGR2 c.-95 CC-genotype. Desmopressin normalized the VWF level of the patient, although its clearance was faster (t(1/2) = 6.7 h) than in normal subjects (t(1/2) = 12 +/- 0.7 h). FVIII-VWF interaction, A Disintegrin And Metalloprotease with ThromboSpondin type 1 motif-13 levels, ristocetin-induced-platelet-aggregation, and VWF multimeric pattern were normal. The p.P1127S variant was normally synthesized and secreted by HEK-293 cells, and molecular modeling predicts a conformational change showing higher affinity for the macrophagic scavenger receptor lipoprotein receptor-related protein 1 (LRP1), as also experimentally verified. Conclusions The p.P1127S variant may cause a low VWF phenotype, stemming from an increased VWF affinity for the scavenger receptor LRP1 and, consequently, an accelerated clearance of VWF.
KW - asialoglycoprotein receptor 2
KW - lipoprotein receptor-related protein 1
KW - protein conformation
KW - scavenger receptors
KW - von Willebrand disease
KW - von Willebrand factor
KW - asialoglycoprotein receptor 2
KW - lipoprotein receptor-related protein 1
KW - protein conformation
KW - scavenger receptors
KW - von Willebrand disease
KW - von Willebrand factor
UR - http://hdl.handle.net/10807/231863
U2 - 10.1111/jth.15765
DO - 10.1111/jth.15765
M3 - Article
SN - 1538-7836
VL - 20
SP - 1818
EP - 1829
JO - Journal of Thrombosis and Haemostasis
JF - Journal of Thrombosis and Haemostasis
ER -