A new type of plasma prekallikrein deficiency associated with homozygosity for Gly104Arg and Asn124Ser in apple domain 2 of the heavy‐chain region

Factor XI (FXI) is the zymogen of an enzyme (FXIa) that contributes to hemostasis by activating factor IX. Although bleeding associated with FXI deficiency is relatively mild, there has been resurgence of interest in FXI because of studies indicating it makes contributions to thrombosis and other processes associated with dysregulated coagulation. FXI is an unusual dimeric protease, with structural features that distinguish it from vitamin K-dependent coagulation proteases. The recent availability of crystal structures for zymogen FXI and the FXIa catalytic domain have enhanced our understanding of structure-function relationships for this molecule. FXI contains 4 "apple domains" that form a disk structure with extensive interfaces at the base of the catalytic domain. The characterization of the apple disk structure, and its relationship to the catalytic domain, have provided new insight into the mechanism of FXI activation, the interaction of FXIa with the substrate factor IX, and the binding of FXI to platelets. Analyses of missense mutations associated with FXI deficiency have provided additional clues to localization of ligand-binding sites on the protein surface. Together, these data will facilitate efforts to understand the physiology and pathology of this unusual protease, and development of therapeutics to treat thrombotic disorders. (Blood. 2010; 115(13):2569-2577) IntroductionFactor XI (FXI) is the zymogen of a blood coagulation protease, factor XIa (FXIa), that contributes to hemostasis through activation of factor IX (FIX; Figure 1). [1][2][3] The protein is a 160-kDa disulfide-linked dimer of identical 607 amino acid subunits, each containing 4 90-or 91-amino acid repeats called apple domains (A1 to A4 from the N-terminus) and a C-terminal trypsin-like catalytic domain. [3][4][5][6][7] The structure is distinctly different from those of the well-characterized vitamin K-dependent coagulation proteases. 1 FXI circulates in blood as a complex with high molecular weight kininogen (HK). 8 Prekallikrein (PK), the zymogen of the protease ␣-kallikrein, is a monomeric homolog of FXI with the same domain structure 9,10 that also circulates in complex with HK. 11 A recent analysis of vertebrate genomes confirmed that FXI and PK are products of a duplication event during mammalian evolution. 12 The ancestral predecessor is also a protease with 4 apple domains, but its functional properties have not been studied. 12 In the cascade/waterfall models of coagulation that are the basis for the activated partial thromboplastin time (aPTT) assay, FXI activation by FXIIa initiates fibrin formation (Figure 1). 1 However, newer schemes do not assign FXI a role in early fibrin generation, based largely on the observation that FXI deficiency causes relatively mild bleeding. [1][2][3] FXIa is now postulated to be part of a feedback loop that sustains thrombin generation through FIX activation to consolidate coagulation (Figure 1). [13][14][15] This appears to be particularly important in tissues with robust fibrinolytic acti...

show abstract

“…A Gly104Arg mutation in the PK A2 domain associated with CRM ϩ PK deficiency also causes decreased HK binding. 74 …”

Section: Fxi and Pk Binding To Hkmentioning

confidence: 99%

Structure and function of factor XI

Emsley

McEwan

Gailani

2010

Blood

195

234

View full text Add to dashboard Cite

show abstract

“…We found the sentinel SNP at the KLKB1 locus to be in complete LD (r 2 =1.00), with an nsSNP (rs3733402) causing an asparagine to serine amino acid substitution (at position 124), located within the functional catalytic domain of plasma kallikrein. This amino acid substitution is known to modify the proteolytic activity of kallikrein, 21 suggesting that the KLKB1 locus is associated with MR-pro-ADM and CT-pro-ET-1 because of differences in cleavage, similar to bradykinin and renin.…”

Section: Discussionmentioning

confidence: 99%

“…We tested the hypothesis that KLKB1 is the causal gene related to the observed association with MR-pro-ADM and CT-pro-ET-1 trough cleavage because (1) KLKB1 encodes a cleavage protein with cleavage sites that overlap with cleavage sites of the precursors of MR-pro-ADM and CT-pro-ET-1, 3,4,17,18 (2) previous GWA publications associated bradykinin 19 and renin levels 20 to the same variant, and (3) the sentinel SNP is in full LD with a coding SNP 21 affecting the proteolytic activity of plasma kallikrein. For this purpose, we designed an in vitro assay.…”

Section: Novel Role Of Klkb1 On Pro-adm and Pro-et-1 Cleavagementioning

confidence: 99%

Genome-Wide Association Study on Plasma Levels of Midregional-Proadrenomedullin and C-Terminal-Pro-Endothelin-1

et al. 2013

View full text Add to dashboard Cite

Abstract-Endothelin-1 (ET-1) and adrenomedullin (ADM) are circulating vasoactive peptides involved in vascular homeostasis and endothelial function. Elevated levels of plasma ET-1 and ADM, and their biologically stable surrogates, C-terminal-pro-endothelin-1 (CT-pro-ET-1) and midregional proadrenomedullin (MR-pro-ADM), are predictors of cardiac death and heart failure. We studied the association of common genetic variation with MR-pro-ADM and CTpro-ET-1 by genome-wide association analyses in 3444 participants of European ancestry. We performed follow-up genotyping of single nucleotide polymorphisms (SNPs) that showed suggestive or significant association in the discovery stage in additional 3230 participants. The minor variants in KLKB1 (rs4253238) and F12 (rs2731672), both part of the kallikrein-kinin system, were associated with higher MR-pro-ADM (P=4.46E-52 and P=5.90E-24, respectively) and higher CT-pro-ET-1 levels (P=1. 23E-122 and P=1.26E-67, respectively). Epistasis analyses showed a significant interaction between the sentinel SNP of F12 and KLKB1 for both traits. In addition, a variant near the ADM gene (rs2957692) was associated with MR-pro-ADM (P=1.05E-12) and a variant in EDN-1 (rs5370) was associated with CTpro-ET-1 (P=1.49E-27). The total phenotypic variation explained by the genetic variants was 7.2% for MR-pro-ADM and 14.6% for CT-pro-ET-1. KLKB1 encodes plasma kallikrein, a proteolytic enzyme known to cleave high-molecular-weight kininogen to bradykinin and prorenin to renin. We cloned the precursors of ADM and ET-1 and demonstrated that purified plasma kallikrein can cleave these recombinant proteins into multiple smaller peptides. The discovery of genetic variants in the kallikrein-kinin system and in the genes encoding pre-pro-ET-1 and pre-pro-ADM provides novel insights into the

show abstract

“…The mutation observed in this dog lead to amino acid substitution in the apple domain 4, which is one of the important regions for the activation of HMWK in humans [12]. Mutations of PK have been found in several regions in human patients with PK deficiency [8]. F330I mutation has not been reported in humans, but phenylalanine at 330 was found to be conserved between species (Fig.…”

mentioning

confidence: 86%

“…This indicates that simultaneous deficiency of both factors could cause the clinical symptoms, even when sole deficiency of FXII or PK does not show any symptoms. PK deficiency has been identified more frequently in humans than in dogs [8] and is found incidentally, reflecting that the affected patients did not have any hemostatic disorders. If hemostatic examination was performed routinely in veterinary clinics for small animals, PK deficiency could be identified to a greater extent.…”

mentioning

confidence: 99%

Prekallikrein Deficiency in a Dog

et al. 2011

View full text Add to dashboard Cite

ABSTRACT. Prekallikrein (PK) deficiency is an uncommon disorder in dogs. In this report, we describe a case of a dog that was referred for neurological defects and had a prolonged activated partial thromboplastin time (aPTT) and normal prothrombin time (PT) with no hemostatic defects. By using human PK-deficient plasma, the dog was diagnosed to have PK deficiency. The nucleotide sequence of normal canine PK cDNA was determined and compared with the genomic sequences of PK in the affected dog. The comparison revealed that the dog had a point mutation in exon 8 that leads to an amino acid substitution in the fourth apple domain of PK. This is the first report showing a point mutation of PK in a dog with PK deficiency.KEY WORDS: canine, mutation, prekallikrein deficiency.

show abstract

A new type of plasma prekallikrein deficiency associated with homozygosity for Gly104Arg and Asn124Ser in apple domain 2 of the heavy‐chain region

Cited by 41 publications

References 28 publications

Structure and function of factor XI

Structure and function of factor XI

Genome-Wide Association Study on Plasma Levels of Midregional-Proadrenomedullin and C-Terminal-Pro-Endothelin-1

Prekallikrein Deficiency in a Dog

Contact Info

Product

Resources

About