Alternative titles; symbols
HGNC Approved Gene Symbol: HABP2
Cytogenetic location: 10q25.3 Genomic coordinates (GRCh38) : 10:113,550,831-113,589,602 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q25.3 | {?Thyroid cancer, nonmedullary, 5} | 616535 | Autosomal dominant | 3 |
| {Venous thromboembolism, susceptibility to} | 188050 | Autosomal dominant | 3 |
Hyaluronic acid is a glycosaminoglycan that is present in the extracellular matrix, connective tissue, cartilage, bone marrow, and synovial fluid. By searching for hyaluronic acid-binding proteins in human plasma, Choi-Miura et al. (1996) identified, purified, and partially sequenced a novel protein, HABP2, which they called PHBP. By SDS-PAGE under nonreducing conditions, they demonstrated that purified HABP2 has a molecular mass of 70 kD; under reducing conditions, HABP2 migrates as 50- and 17-kD polypeptides, indicating that HABP2 is a heterodimer whose subunits are joined by disulfide bonds. By screening a human liver cDNA library using degenerate oligonucleotides based on the HABP2 amino acid sequence, they cloned HABP2. The deduced full-length 560-amino acid protein contains a signal peptide, 3 EGF domains, a kringle domain, and a serine protease domain. HABP2 has a calculated molecular mass of about 63 kD. Northern blot analysis indicated that HABP2 is expressed as 3.0- and 2.3-kb mRNAs in human kidney, liver, and pancreas.
Choi-Miura et al. (2001) found that after incubation of HABP2 purified from human plasma, the single 70-kD protein fragmented into a 50-kD N-terminal fragment and a 27-kD C-terminal fragment, and this was followed by cleavage of the 50-kD fragment into two 26-kD fragments and cleavage of the 27-kD fragment into 17- and 8-kD fragments. Because the purified protein contained no other detectable proteins and HABP2 has a typical serine protease domain, Choi-Miura et al. (2001) concluded that fragmentation of HABP2 was caused by autoproteolysis. They further determined that the single-chain form of HABP2 is a precursor, the 2-subunit structure is the active serine protease, and the 3- or 4-chain structures are inactive.
Romisch et al. (2001) noted that a protease that they had named factor VII-activating protease (FSAP), due to its potent activation of factor VII, was 'identical or closely related to' PHBP.
Using SDS-PAGE, Choi-Miura et al. (2001) demonstrated that fibrinogen (see FGA; 134820) and fibronectin (135600) are the major substrates of PHBP. PHBP cleaved the fibrinogen alpha chain (FGA) at multiple sites and the beta chain (FGB; 134830) between lys53 and lys54, but not the gamma chain (FGG; 134850); thus, PHBP does not initiate the formation of fibrin clot and does not cause fibrinolysis directly. PHBP did not cleave prothrombin (176930) or plasminogen (173350), but it converted the inactive single-chain urinary plasminogen activator (UPA; 191840) to the active 2-chain form.
Sumiya et al. (1997) determined that the HABP2 gene contains 13 exons and spans 35 kb.
By FISH, Sumiya et al. (1997) mapped the HABP2 gene to chromosome 10q25-q26.
Nonmedullary Thyroid Cancer
In a large multiplex family with familial nonmedullary thyroid cancer (NMTC5; 616535), Gara et al. (2015) found a heterozygous missense mutation in the HABP2 gene (G534E; 603924.0001) that segregated with disease in the family. Overexpression of the mutant protein caused increased colony formation and cellular migration compared to wildtype. Analysis of data from the Cancer Genome Atlas (TCGA) in 423 patients with papillary thyroid cancer showed that 4.7% carried the HABP2 G534E variant, as compared with 0.7% of individuals with unknown disease status in multiethnic population databases (p less than 0.001). This suggested to Gara et al. (2015) that the HABP2 G534E germline variant may be a susceptibility gene for additional cases of familial nonmedullary thyroid cancer.
Zhou et al. (2015), Sponziello et al. (2015), and Tomsic et al. (2015) stated that the allele frequency of the G534E variant exceeds the filtering criterion used by Gara et al. (2015); see 603924.0001.
Role in Fibrinolysis
In 10% of plasma samples from 189 healthy individuals from Marburg, Germany, Romisch et al. (2001) found a greater than 50% reduction in the plasma activity of FSAP. Analysis of purified FSAP from 3 unrelated donors with reduced plasma activity confirmed the results and suggested the presence of a polymorphism.
In 24 healthy individuals with normal plasma FSAP levels but reduced pro-urokinase activation, Roemisch et al. (2002) identified heterozygosity for a polymorphism in exon 13 of the FSAP gene (603294.0001), which they termed the Marburg I (MI) variant.
Sedding et al. (2006) compared the effects of local application of wildtype FSAP and FSAP with the MI polymorphism to mouse femoral artery after wire-induced injury. Wildtype FSAP-treated arteries exhibited a 70% reduction of neointima formation after injury. In contrast, MI-FSAP failed to inhibit neointima formation due to reduced protease activity toward platelet-derived growth factor BB (see PDGFB, 190040). Sedding et al. (2006) concluded that the inability of MI-FSAP to inhibit vascular smooth muscle accumulation explains the linkage between MI-FSAP and increased cardiovascular risk.
Nonmedullary Thyroid Cancer
By whole-exome sequencing followed by Sanger sequencing, Gara et al. (2015) identified a 1601G-A transition in exon 13 of the HABP2 gene resulting in a gly534-to-glu (G534E) amino acid substitution in affected members of a 3-generation family segregating autosomal dominant familial nonmedullary thyroid cancer (NMTC5; 616535). All affected family members were heterozygous for the variant in peripheral blood DNA. This mutation was found with an allele frequency of 0.02223 in the ExAC Browser, and in 4.7% of 423 patients with thyroid cancer reported in TCGA data. The G534E mutation occurs within the serine protease trypsin domain of the HABP2 protein. Homologic modeling showed that the mutation results in a space constraint near the catalytic region, thereby disrupting the active site and surface accessibility of its substrates. Immunohistochemical analysis showed increased HABP2 protein expression in papillary thyroid cancers (PTCs) and follicular adenoma tumors from affected family members, but there was no staining in normal thyroid tissue from the same affected members. In contrast, only 3 of 12 sporadic PTCs had faint HABP2 protein staining. Transient knockdown of wildtype HABP2 in 3 different human cell lines (follicular thyroid cancer, PTC, and embryonic kidney) increased colony formation and cellular migration, suggesting a tumor-suppressive function. Stable overexpression of wildtype HABP2 protein in cell lines reduced colony formation and cellular migration, while overexpression of G534E mutant protein increased colony formation. Foci assays in NIH-3T3 cells demonstrated that the G534E variant induced a significantly higher number of foci and increased cellular migration compared with wildtype. Cotransfection with equal amounts of wildtype and G534E mutant constructs into NIH-3T3 cells resulted in greater foci formation and cellular migration than in wildtype HABP2 overexpression, suggesting a dominant-negative effect of the mutation.
Zhou et al. (2015), Sponziello et al. (2015), and Tomsic et al. (2015) stated that the allele frequency of the G534E variant exceeds the filtering criterion used by Gara et al. (2015) (less than 1% in public databases). Gara et al. (2015) reported an incidence of the G534E variant of 0.7% in the 1000 Genomes Project and HapMap3 databases; Zhou et al. (2015) noted that the frequency in the ExAC database among non-Finnish Europeans is 3.29%. Gara and Kebebew (2015) responded that the ExAC browser includes data from 60,706 persons, 7,601 of whom were patients with cancer that were included in the Cancer Genome Atlas database (12.5%). They also commented that thyroid cancer is a very common condition depending on screening methods used and that the purpose of their study was to report a kindred in whom thyroid cancer segregated with the allele and was very aggressive.
Zhao et al. (2015) noted that the G534E variant was not seen in any Chinese patients with thyroid cancer.
Role in Fibrinolysis
In 24 healthy individuals with normal plasma FSAP levels but reduced pro-urokinase activation, Roemisch et al. (2002) identified heterozygosity for a 1601G-A transition in exon 13 of the HABP2 gene, resulting in a gly534-to-glu (G534E) substitution near the C terminus of the light chain. The authors referred to the mutation as G511E, using the amino acid numbering of the mature protein produced by excision of the 23-amino acid signal peptide.
Willeit et al. (2003) analyzed the Marburg I polymorphism in 810 men and women, aged 40 to 79 years, who had participated in an ultrasound study of atherosclerosis. The Marburg I polymorphism was found in 37 (4.4%) individuals, who showed a prominently reduced in vitro capacity to activate pro-urokinase. No relation was found between the Marburg I polymorphism and early atherogenesis; however, it was a strong and independent risk predictor of incident/progressive carotid stenosis.
Hoppe et al. (2005) found that the frequency of the Marburg I polymorphism was significantly increased in patients with a history of venous thromboembolism (see 188050).
Choi-Miura, N.-H., Takahashi, K., Yoda, M., Saito, K., Mazda, T., Tomita, M. Proteolytic activation and inactivation of the serine protease activity of plasma hyaluronan binding protein. Biol. Pharm. Bull. 24: 448-452, 2001. [PubMed: 11379758] [Full Text: https://doi.org/10.1248/bpb.24.448]
Choi-Miura, N.-H., Tobe, T., Sumiya, J., Nakano, Y., Sano, Y., Mazda, T., Tomita, M. Purification and characterization of a novel hyaluronan-binding protein (PHBP) from human plasma: it has three EGF, a kringle and a serine protease domain, similar to hepatocyte growth factor activator. J. Biochem. 119: 1157-1165, 1996. [PubMed: 8827452] [Full Text: https://doi.org/10.1093/oxfordjournals.jbchem.a021362]
Choi-Miura, N.-H., Yoda, M., Saito, K., Takahashi, K., Tomita, M. Identification of the substrates for plasma hyaluronan binding protein. Biol. Pharm. Bull. 24: 140-143, 2001. [PubMed: 11217080] [Full Text: https://doi.org/10.1248/bpb.24.140]
Gara, S. K., Jia, L., Merino, M. J., Agarwal, S. K., Zhang, L., Cam, M., Patel, D., Kebebew, E. Germline HABP2 mutation causing familial nonmedullary thyroid cancer. New Eng. J. Med. 373: 448-455, 2015. [PubMed: 26222560] [Full Text: https://doi.org/10.1056/NEJMoa1502449]
Gara, S. K., Kebebew, E. HABP mutation and nonmedullary thyroid cancer. New Eng. J. Med. 373: 2086-2087, 2015. [PubMed: 26581001] [Full Text: https://doi.org/10.1056/NEJMc1511631]
Hoppe, B., Tolou, F., Radtke, H., Kiesewetter, H., Dorner, T., Salama, A. Marburg I polymorphism of factor VII-activating protease is associated with idiopathic venous thromboembolism. Blood 105: 1549-1551, 2005. [PubMed: 15486068] [Full Text: https://doi.org/10.1182/blood-2004-08-3328]
Roemisch, J., Feussner, A., Nerlich, C., Stoehr, H.-A., Weimer, T. The frequent Marburg I polymorphism impairs the pro-urokinase activating potency of the factor VII activating protease (FSAP). Blood Coagul. Fibrinolysis 13: 433-441, 2002. [PubMed: 12138371] [Full Text: https://doi.org/10.1097/00001721-200207000-00008]
Romisch, J., Feussner, A., Stohr, H. A. Quantitation of the factor VII- and single-chain plasminogen activator-activating protease in plasmas of healthy subjects. Blood Coagul. Fibrinolysis 12: 375-383, 2001. [PubMed: 11505081] [Full Text: https://doi.org/10.1097/00001721-200107000-00007]
Sedding, D., Daniel, J.-M., Muhl, L., Hersemeyer, K., Brunsch, H., Kemkes-Matthes, B., Braun-Dullaeus, R. C., Tillmanns, H., Weimer, T., Preissner, K. T., Kanse, S. M. The G534E polymorphism of the gene encoding the factor VII-activating protease is associated with cardiovascular risk due to increased neointima formation. J. Exp. Med. 203: 2801-2807, 2006. [PubMed: 17145954] [Full Text: https://doi.org/10.1084/jem.20052546]
Sponziello, M., Durante, C., Filetti, S. HABP mutation and nonmedullary thyroid cancer. New Eng. J. Med. 373: 2085-2086, 2015. [PubMed: 26581004] [Full Text: https://doi.org/10.1056/NEJMc1511631]
Sumiya, J., Asakawa, S., Tobe, T., Hashimoto, K., Saguchi, K., Choi-Miura, N.-H., Shimizu, Y., Minoshima, S., Shimizu, N., Tomita, M. Isolation and characterization of the plasma hyaluronan-binding protein (PHBP) gene (HABP2). J. Biochem. 122: 983-990, 1997. [PubMed: 9443814] [Full Text: https://doi.org/10.1093/oxfordjournals.jbchem.a021861]
Tomsic, J., He, H., de la Chapelle, A. HABP mutation and nonmedullary thyroid cancer. New Eng. J. Med. 373: 2086 only, 2015. [PubMed: 26581005] [Full Text: https://doi.org/10.1056/NEJMc1511631]
Willeit, J., Kiechl, S., Weimer, T., Mair, A., Santer, P., Wiedermann, C. J., Roemisch, J. Marburg I polymorphism of factor VII-activating protease: a prominent risk predictor of carotid stenosis. Circulation 107: 667-670, 2003. [PubMed: 12578864] [Full Text: https://doi.org/10.1161/01.cir.0000055189.18831.b1]
Zhao, X., Li, X., Zhang, X. HABP mutation and nonmedullary thyroid cancer. New Eng. J. Med. 373: 2084 only, 2015. [PubMed: 26581002] [Full Text: https://doi.org/10.1056/NEJMc1511631]
Zhou, E. Y., Lin, Z., Yang, Y. HABP mutation and nonmedullary thyroid cancer. New Eng. J. Med. 373: 2084-2085, 2015. [PubMed: 26581003] [Full Text: https://doi.org/10.1056/NEJMc1511631]