Alternative titles; symbols
Other entities represented in this entry:
SNOMEDCT: 27312002; ORPHA: 483; DO: 0111676;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3q27.3 | [High molecular weight kininogen deficiency] | 228960 | Autosomal recessive | 3 | KNG1 | 612358 |
| 3q27.3 | [Kininogen deficiency] | 228960 | Autosomal recessive | 3 | KNG1 | 612358 |
A number sign (#) is used with this entry because high molecular weight kininogen deficiency and total kininogen deficiency result from mutations in the kininogen-1 gene (KNG1; 612358).
High molecular weight kininogen (HMWK) deficiency is an autosomal recessive coagulation defect. It is known by a variety of names, including Fitzgerald trait, Flaujeac trait, and Williams trait. Patients with HWMK deficiency do not have a hemorrhagic tendency, but they exhibit abnormal surface-mediated activation of fibrinolysis. Fitzgerald trait represents a 'true' deficiency of HMWK, whereas Flaujeac and Williams traits represent total kininogen deficiency, in which both HMWK and low molecular weight kininogen (LMWK) are deficient. HMWK and LMWK are both encoded by the KNG1 gene (612358) (Bick, 2002; Takagaki et al., 1985).
Lacombe et al. (1975) described deficiency of a procoagulant they called Flaujeac factor, which, like Hageman (F12; 610619) and Fletcher (KLKB1; 229000) factors, participated in the 'contact phase' of coagulation. The deficiency was observed in an asymptomatic French woman born of a consanguineous marriage. Wuepper et al. (1975) showed that 4 children of the proposita had total kininogen antigen about half normal, consistent with autosomal recessive inheritance.
Waldmann et al. (1975) and Saito et al. (1975) described a 'new' asymptomatic coagulation factor deficiency in a 71-year-old black man of surname Fitzgerald. The factor seemed to operate at an early stage in the intrinsic coagulation pathway and participated in other Hageman factor-mediated biologic reactions. No family data were presented. His plasma was apparently deficient in a hitherto unrecognized factor needed for expression of the functions of activated Hageman factor.
Colman et al. (1975) studied an asymptomatic 64-year-old black woman of the surname Williams, who had severe abnormality of surface-activated intrinsic coagulation, and fibrinolytic and kinin-generating pathways. Fractionation of normal plasma showed that the factor that corrected the defect in Ms. Williams' plasma was kininogen. The proband was ascertained when a prolonged partial thromboplastin time was detected as part of a routine preoperative evaluation of her hemostatic mechanism. Members of her family were not available for study. However, Cheung et al. (1993) had 3 daughters and 1 granddaughter available for study when they reinvestigated the proband.
Lefrere et al. (1986) discovered HMWK deficiency in the course of a preoperative hemostasis study of a 23-year-old Portuguese woman without personal or family history of hemorrhage or thrombosis. Family study showed heterozygous HMWK deficiency in the proposita, her father, and 3 of her sibs.
Hayashi et al. (1990) studied 4 Japanese families with total kininogen deficiency and 1 with deficiency of HMWK only.
Krijanovski et al. (2003) reported a 6-year-old male, born of first-cousin parents, with cerebral artery thrombosis and HMWK deficiency. The previously healthy child had headache and vomiting 10 days after moderate cerebral trauma, followed by loss of consciousness and subsequent visual impairment. CT scan and angiography showed extensive left vertebral-basilar artery thrombosis and a left vertebral artery dissection. The patient had a prolonged activated partial thromboplastin time (APTT) and received fresh frozen plasma before arteriography and then daily for 8 days, which resulted in normalization of the APTT and resolution of neurologic symptoms. There was full neurologic recovery with warfarin anticoagulant therapy for 6 months, and there had been no recurrence after 2 years of follow-up. The child had no high molecular weight kininogen procoagulant activity and antigen (less than 1%).
HMWK deficiency results from mutation in the KNG1 gene, which maps to chromosome 3q26-qter (Fong et al., 1991; Cheung et al., 1992).
Cheung et al. (1993) demonstrated that Ms. Williams, the patient with total kininogen deficiency reported as Williams trait by Colman et al. (1975), was homozygous for a nonsense mutation in the KNG1 gene (612358.0001).
Krijanovski et al. (2003) found that a 6-year-old boy with cerebral artery thrombosis and HMWK deficiency was homozygous for a 1-bp deletion of 1492A in the KNG1 gene (612358.0002), corresponding to amino acid 480 of the mature protein. The mutation resulted in a frameshift and premature termination at amino acid 532 of the mature protein. Each parent and a sib were heterozygous for the mutation. Krijanovski et al. (2003) also identified the causative mutation in Fitzgerald trait as a 17-bp substitution in intron 9 of the KNG1 gene (612358.0003). They provided a diagram comparing the molecular defects of Williams trait (612358.0001), their reported deletion of 1492A, and Fitzgerald trait with normal HMWK.
Bick, R. L. Disorders of Thrombosis and Hemostasis: Clinical and Laboratory Practice. (3rd ed.) Philadelphia: Lippincott, Williams and Wilkins (pub.) 2002. P. 127.
Cheung, P. P., Cannizzaro, L. A., Colman, R. W. Chromosomal mapping of human kininogen gene (KNG) to 3q26-qter. Cytogenet. Cell Genet. 59: 24-26, 1992. [PubMed: 1733668] [Full Text: https://doi.org/10.1159/000133192]
Cheung, P. P., Kunapuli, S. P., Scott, C. F., Wachtfogel, Y. T., Colman, R. W. Genetic basis of total kininogen deficiency in Williams' trait. J. Biol. Chem. 268: 23361-23365, 1993. [PubMed: 7901207]
Colman, R. W., Bagdasarian, A., Talamo, R. C., Scott, C. F., Seavey, M., Guimaraes, J. A., Pierce, J. V., Kaplan, A. P. Williams trait: human kininogen deficiency with diminished levels of plasminogen proactivator and prekallikrein associated with abnormalities of the Hageman factor dependent pathways. J. Clin. Invest. 56: 1650-1662, 1975. [PubMed: 1202089] [Full Text: https://doi.org/10.1172/JCI108247]
Donaldson, V. H., Kleniewski, J., Saito, H., Sayed, J. K. Prekallikrein deficiency in a kindred with kininogen deficiency and Fitzgerald trait clotting defect: evidence that high molecular weight kininogen and prekallikrein exist as a complex in normal plasma. J. Clin. Invest. 60: 571-583, 1977. [PubMed: 893663] [Full Text: https://doi.org/10.1172/JCI108809]
Fong, D., Smith, D. I., Hsieh, W.-T. The human kininogen gene (KNG) mapped to chromosome 3q26-qter by analysis of somatic cell hybrids using the polymerase chain reaction. Hum. Genet. 87: 189-192, 1991. [PubMed: 2066106] [Full Text: https://doi.org/10.1007/BF00204179]
Hayashi, H., Ishimaru, F., Fujita, T., Tsurumi, N., Tsuda, T., Kimura, I. Molecular genetic survey of five Japanese families with high molecular weight kininogen deficiency. Blood 75: 1296-1304, 1990. [PubMed: 1968772]
James, F. W., Donaldson, V. H. Decreased exercise tolerance and hypertension in severe hereditary deficiency of plasma kininogens. (Letter) Lancet 317: 889 only, 1981. Note: Originally Volume I. [PubMed: 6112306] [Full Text: https://doi.org/10.1016/s0140-6736(81)92154-1]
Krijanovski, Y., Proulle, V., Mahdi, F., Dreyfus, M., Muller-Esterl, W., Schmaier, A. H. Characterization of molecular defects of Fitzgerald trait and another novel high-molecular-weight kininogen-deficient patient: insights into structural requirements for kininogen expression. Blood 101: 4430-4436, 2003. [PubMed: 12576314] [Full Text: https://doi.org/10.1182/blood-2002-11-3329]
Lacombe, M.-J., Varet, B., Levy, J.-P. A hitherto undescribed plasma factor acting at the contact phase of blood coagulation (Flaujeac factor): case report and coagulation studies. Blood 46: 761-768, 1975. [PubMed: 1174709]
Lefrere, J.-J., Horellou, M.-H., Gozin, D., Conard, J., Muller, J.-Y., Clark, M., Soulier, J.-P., Samama, M. A new case of high molecular weight kininogen inherited deficiency. Am. J. Hemat. 22: 415-419, 1986. [PubMed: 3728458] [Full Text: https://doi.org/10.1002/ajh.2830220411]
Saito, H., Ratnoff, O. D., Waldmann, R., Abraham, J. P. Deficiency of a hitherto unrecognized agent, Fitzgerald factor, participating in surface-medicated reactions of clotting, fibrinolysis, generation of kinins, and the property of diluted plasma enhancing vascular permeability (Pf-DIL). J. Clin. Invest. 55: 1082-1089, 1975. [PubMed: 16695963] [Full Text: https://doi.org/10.1172/JCI108009]
Takagaki, Y., Kitamura, N., Nakanishi, S. Cloning and sequence analysis of cDNAs for human high molecular weight and low molecular weight prekininogens: primary structures of two human prekininogens. J. Biol. Chem. 260: 8601-8609, 1985. [PubMed: 2989293]
Waldmann, R., Abraham, J. P., Rebuck, J. W., Caldwell, J., Saito, H., Ratnoff, O. D. Fitzgerald factor: a hitherto unrecognized coagulation factor. Lancet 305: 949-951, 1975. Note: Originally Volume I. [PubMed: 48123] [Full Text: https://doi.org/10.1016/s0140-6736(75)92008-5]
Wuepper, K. D., Miller, D. R., Lacombe, M. J. Flaujeac trait: deficiency of human plasma kininogen. J. Clin. Invest. 56: 1663-1672, 1975. [PubMed: 127805] [Full Text: https://doi.org/10.1172/JCI108248]