Other entities represented in this entry:
ORPHA: 217467; DO: 0111903;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3q27.3 | Thrombophilia 11 due to HRG deficiency | 613116 | Autosomal dominant | 3 | HRG | 142640 |
A number sign (#) is used with this entry because of evidence that thrombophilia due to histidine-rich glycoprotein deficiency (THPH11) is caused by heterozygous mutation in the HRG gene (142640) on chromosome 3q27.
Shigekiyo et al. (1993) identified a family with congenital HRG deficiency. The proband, a 43-year-old woman, suffered from right transverse sinus thrombosis during oral contraceptive treatment. Affected members of the family (5 in 3 generations) had plasma HRG levels 25 to 35% of normal. Shigekiyo et al. (1995) could demonstrate no abnormalities in hemostatic screening tests, activities of natural anticoagulants and fibrinolytic proteins, markers of thrombin and plasmin generation, plasma levels of platelet-specific proteins, thrombin times with various concentrations of bovine thrombin, prolongation of thrombin time after addition of heparin or dermatan sulfate, and contact activation of blood coagulation in 5 'affected' members of the family.
Souto et al. (1996) described a family with decreased levels of HRG in 4 individuals of 3 generations. The family was brought to their attention by a woman who had developed pulmonary embolism twice at the age of 36 years. Her father had thrombosis of the central retinal artery at the age of 59 years. None of the individuals in the family was under drug therapy or affected by inflammatory diseases able to modify the plasma concentration of HRG.
Shigekiyo et al. (2000) reported a 76-year-old Japanese woman with a dural arteriovenous fistula associated with plasma HRG deficiency. Her daughter also had plasma HRG deficiency, but was asymptomatic.
Luo et al. (2018) reported a 41-year-old man who complained of repeated left lower extremity swelling and itching. Physical examination revealed brownish skin discoloration around the ankle. At the age of 19, he reportedly had an episode of progressive pain and swelling of the left leg with no history of trauma or immobilization. Deep venous angiography showed occlusion of deep veins accompanied by marked collateral vessel formation. His father and 2 sibs had been diagnosed with deep venous thrombosis at the age of 29, 26, and 22, respectively. Plasma levels of HRG in affected individuals were approximately half of those in unaffected controls.
Thrombophilia due to Elevated HRG
Engesser et al. (1987) described a family with thrombophilia and elevated levels of HRG in 5 persons in 3 sibships of 2 generations. By history a third generation was affected, and the apparent involvement of a deceased member represented male-to-male transmission.
Falkon et al. (1992) described a similar family in which high levels of the HRG protein was demonstrated. The family was brought to attention by a 41-year-old woman who had had recurrent thromboembolic disease starting at the age of 22 years. She was also shown to have elevation of plasminogen activator inhibitor-1 (PAI1; 173360), which was not detected in any other member of the family. Falkon et al. (1992) suggested that elevated HRG may not be a strong risk factor for venous thrombosis when it is not combined with another defect.
Angles-Cano et al. (1993) found high levels of HRG and PAI1 in 8 and 10 members, respectively, of a family from which 4 of 7 members with both abnormalities had venous thromboembolism. On the basis of their studies, they concluded that the excess HRG was probably not related to the thromboembolic events.
Hoffmann et al. (1993) found persistently elevated levels of plasma HRG in a 64-year-old female with a history of recurrent arterial thromboembolic events. Increased HRG was found in 8 of 17 relatives studied, but none of them had experienced thromboembolism. Increased HRG was inherited as an autosomal dominant. The plasma HRG of the proposita and 9 of her family members displayed abnormal binding to heparin, as assessed in a crossed affinity immunoelectrophoresis system; the usual increase in mobility after binding to heparin was absent. The binding of the variant HRG to plasminogen was normal. This was the first example of an abnormal HRG variant. The authors proposed the designation HRG-Eindhoven for the variant.
Castaman et al. (1993) described 2 families with a history of thrombosis and high levels of HRG. The propositus of family 1 died of massive pulmonary embolism at age 34. His mother and maternal grandmother suffered from deep and superficial vein thrombosis (DVT/SVT) in their youth. High levels of HRG were found in the mother, 3 of the proband's sibs, and 2 of his nephews. In family 2, the proposita suffered from spontaneous DVT at age 24. The paternal grandmother and a paternal aunt had several episodes of SVT and DVT. High levels of HRG cosegregated with thrombotic symptoms.
Ehrenforth et al. (1994) evaluated the prevalence of elevated plasma HRG levels over a 5-year period in 695 patients suffering from thrombophilia. The plasma level of HRG was consistently higher in 10.8% of all investigated patients than in a group of 60 healthy individuals. Familial elevation of HRG was found in 3 of 10 investigated families.
The transmission pattern of HRG deficiency in the family reported by Shigekiyo et al. (1998) was consistent with autosomal dominant inheritance.
In a 43-year-old woman with HRG deficiency who suffered from right transverse sinus thrombosis during oral contraceptive treatment, Shigekiyo et al. (1998) identified a heterozygous 429G-A transition, which caused a gly85-to-glu substitution (G85E; 142640.0001) in the first cystatin-like domain of the protein. The mutation was found in members of her family with HRG deficiency but not in 50 unrelated healthy Japanese individuals.
In a 76-year-old Japanese woman and her daughter with plasma HRG deficiency, Shigekiyo et al. (2000) identified a heterozygous missense mutation in the HRG gene (C223R; 142640.0002). The variant, which was designated 'Tokushima 2,' was not found in unaffected family members or in 50 control individuals. Expression of the mutant in BHK cells demonstrated that only about 40% of the mutant HRG was secreted compared to wildtype, and that the mutant HRG underwent intracellular degradation. The mother had a dural arteriovenous fistula, which may occur at sites of previous thrombosis; the daughter had no symptoms.
In 4 affected members of a family with early-onset deep venous thrombosis, Luo et al. (2018) identified heterozygosity for a missense mutation (P73S; 142640.0003) in the HRG gene. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family.
Angles-Cano, E., Gris, J. C., Loyau, S., Schved, J. F. Familial association of high levels of histidine-rich glycoprotein and plasminogen activator inhibitor-1 with venous thromboembolism. J. Lab. Clin. Med. 121: 646-653, 1993. [PubMed: 8478593]
Castaman, G., Ruggeri, M., Burei, F., Rodeghiero, F. High levels of histidine-rich glycoprotein and thrombotic diathesis: report of two unrelated families. Thromb. Res. 69: 297-305, 1993. [PubMed: 8475479] [Full Text: https://doi.org/10.1016/0049-3848(93)90027-l]
Ehrenforth, S., Aygoren-Pursun, E., Hach-Wunderle, V., Scharrer, I. Prevalence of elevated histidine-rich glycoprotein in patients with thrombophilia--a study of 695 patients. (Letter) Thromb. Haemost. 71: 160-161, 1994. [PubMed: 8165641]
Engesser, L., Kluft, C., Briet, E., Brommer, E. J. P. Familial elevation of plasma histidine-rich glycoprotein in a family with thrombophilia. Brit. J. Haemat. 67: 355-358, 1987. [PubMed: 3689697] [Full Text: https://doi.org/10.1111/j.1365-2141.1987.tb02357.x]
Falkon, L., Gari, M., Montserrat, I., Borrell, M., Fontcuberta, J. Familial elevation of plasma histidine-rich glycoprotein: a case associated with recurrent venous thrombosis and high PAI-1 levels. Thromb. Res. 66: 265-270, 1992. [PubMed: 1412197] [Full Text: https://doi.org/10.1016/0049-3848(92)90197-i]
Hoffmann, J. J. M. L., Hennis, B. C., Kluft, C., Vijgen, M. Hereditary increase of plasma histidine-rich glycoprotein associated with abnormal heparin binding (HRG Eindhoven). Thromb. Haemost. 70: 894-899, 1993. [PubMed: 8165607]
Luo, J., Zhang, W., Zeng, Q., Zhou, W., Cao, Q., Zhou, W. Familial early-onset deep venous thrombosis associated with a novel HRG mutation. Europ. J. Med. Genet. 61: 68-71, 2018. [PubMed: 29108964] [Full Text: https://doi.org/10.1016/j.ejmg.2017.10.019]
Shigekiyo, T., Kanazuka, M., Azuma, H., Ohshima, T., Kusaka, K., Saito, S. Congenital deficiency of histidine-rich glycoprotein: failure to identify abnormalities in routine laboratory assays of hemostatic function, immunologic function, and trace elements. J. Lab. Clin. Med. 125: 719-723, 1995. [PubMed: 7769366]
Shigekiyo, T., Ohshima, T., Oka, H., Tomonari, A., Azuma, H., Saito, S. Congenital histidine-rich glycoprotein deficiency. Thromb. Haemost. 70: 263-265, 1993. [PubMed: 8236132]
Shigekiyo, T., Yoshida, H., Kanagawa, Y., Satoh, K., Wakabayashi, S., Matsumoto, T., Koide, T. Histidine-rich glycoprotein (HRG) Tokushima 2: novel HRG deficiency, molecular and cellular characterization. Thromb. Haemost. 84: 675-679, 2000. [PubMed: 11057869]
Shigekiyo, T., Yoshida, H., Matsumoto, K., Azuma, H., Wakabayashi, S., Saito, S., Fujikawa, K., Koide, T. HRG Tokushima: molecular and cellular characterization of histidine-rich glycoprotein (HRG) deficiency. Blood 91: 128-133, 1998. [PubMed: 9414276]
Souto, J. C., Gari, M., Falkon, L., Fontcuberta, J. A new case of hereditary histidine-rich glycoprotein deficiency with familial thrombophilia. (Letter) Thromb. Haemost. 75: 374-375, 1996. [PubMed: 8815595]