Detection of two novel mutations (nt2762, exon 2, CAG to TAG, and nt2483 or 2484, exon 2, +A) in individuals with congenital type I antithrombin deficiencies

Nakahara, Yoshifumi; Tsuji, Hiroko; Nakagawa, Kouichi; Masuda, Haruchika; Kitamura, Hidetsugu; Nishimura, Hiroshi; Kasahara, Takehide; Sugano, Tomoko; Sawada, Shuichi; Sakata, Toshiyuki; Miyata, Takamitsu; Inoue, Norihito; Nakagawa, Mayumi

doi:10.1097/00001721-199907000-00002

Cited by 4 publications

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“…In our patient, a novel point mutation was demonstrated in the gene for antithrombin, which had not previously been reported in the database (12) or in other reports (13)(14)(15)(16)(17)(18)(19). Our patient maintained an innate half dose of functional antithrombin, and did not have a history of thrombosis from birth.…”

Section: Discussionsupporting

confidence: 61%

Successful therapy with argatroban for superior mesenteric vein thrombosis in a patient with congenital antithrombin deficiency

Muta

Okamura

Kawamoto

et al. 2005

European J of Haematology

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A 38-year-old woman was admitted with superior mesenteric vein (SMV) thrombosis, which was refractory to anticoagulation therapy. The plasma antithrombin activity was decreased and hardly compensated by concentrated antithrombin preparation due to high consumption rate. However, successful anticoagulation was achieved by administration of direct thrombin inhibitor, argatroban. Family studies of antithrombin activity revealed that she had type I congenital antithrombin deficiency. A novel heterozygous mutation in the gene for antithrombin (single nucleotide T insertion at 7916 and 7917, Glu 272 to stop in exon 4) was identified. Argatroban administration would be effective in the treatment of congenital antithrombin deficiency with SMV thrombosis.

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Section: Discussionsupporting

confidence: 61%

Successful therapy with argatroban for superior mesenteric vein thrombosis in a patient with congenital antithrombin deficiency

Muta

Okamura

Kawamoto

et al. 2005

European J of Haematology

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“…Since Koide et al [10] reported the molecular defect of AT deficiency (AT Toyama, Arg47Cys) for the first time in 1984, more than 150 different AT gene mutations have been identified, about 70% of which belong to type I deficiency [5,[11][12][13][14][15]. Identification of gene mutations occurring in AT-deficient pedigrees and further molecular characterization would give important information on the structure-function relationships of this major hemostatic protein.…”

Section: Discussionmentioning

confidence: 99%

Characterization of molecular defect of 13387-9delG mutated antithrombin in inherited type I antithrombin deficiency

Wang

Ding

et al. 2005

Blood Coagulation &Amp; Fibrinolysis

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As a major physiological inhibitor of thrombin and other coagulation proteases, antithrombin (AT) plays an important role in the maintenance of normal hemostasis and its deficiency is associated with a predisposition for familial venous thromboembolic disease. Recently, we found a novel mutation (13387-9delG) in the antithrombin gene that is associated with type I AT deficiency. To examine the molecular pathologic mechanism of this mutation causing type I AT deficiency, the wild-type and the mutant AT constructs were expressed in COS-7 cells or Chinese Hamster Ovary cells. No AT antigen could be detected by enzyme-linked immunosorbent assay in the conditioned media of cells expressing the mutant protein, and the AT antigen level was reduced in cell lysates. The mutant AT-expressing cells did not have less intracellular mRNA levels than the wild-type transfectants as estimated by quantitative reverse transcriptase-polymerase chain reaction. Metabolic and pulse-chase experiments showed the newly synthesized wild-type AT protein was gradually secreted into the media, whereas no labeled mutant AT protein was detected in the media and the total amount of radioactivity was significantly reduced in the cells during the chase periods. By immunofluorescence analysis, the staining of the mutant AT was weaker than that of the wild type, and was predominantly diffuse without perinuclear enhancement. These results indicate that the 13387-9delG mutation, which disrupts the disulfide bridge Cys247-Cys430, impairs the secretion and stability of the truncated AT protein associated with intracellular degradation.

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Two Novel Gene Mutations in Type I Antithrombin Deficiency

et al. 2001

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We studied the molecular basis of type I antithrombin (AT) deficiency in 2 Japanese families, in which affected persons had histories of recurrent venous thrombosis and low (about 50% of normal) levels of AT protein according to measurements by both functional and antigen assays. Southern blotting of DNA isolated from peripheral leukocytes revealed no abnormalities in all the cases examined. Direct sequencing of the polymerase chain reaction (PCR) products from case I suggested a novel heterozygous nonsense mutation in exon 4 (GAG-->TAG at nucleotide position 7627, leading to Glu306 stop). The sequencing of the subclones of the patient's exon 4 products confirmed the nonsense mutation. No other sequence abnormalities were detected in the rest of the PCR products. The same mutation was detected in this patient's brother, who had a history of recurrent venous thrombosis and a reduced level of AT activity. In case 2, the direct sequencing of PCR products suggested a novel heterozygous 9-bp deletion in exon 3a (-CACTTC at nucleotide position 5354-5362, leading to the deletion of 3 amino acids, His120, Phel21, and Phe122). The 9-bp deletion mutation in the region of a unique quasi palindrome was confirmed by sequencing several of the subclones of the patient's exon 3a from the PCR products. No other mutations were found by direct sequencing of the rest of the coding regions. The 2 mutations found in this study are novel. The use of PCR and the sequencing of the PCR product subclones has simplified and confirmed the detection and characterization of the various AT mutations.

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Detection of two novel mutations (nt2762, exon 2, CAG to TAG, and nt2483 or 2484, exon 2, +A) in individuals with congenital type I antithrombin deficiencies

Cited by 4 publications

References 0 publications

Successful therapy with argatroban for superior mesenteric vein thrombosis in a patient with congenital antithrombin deficiency

Successful therapy with argatroban for superior mesenteric vein thrombosis in a patient with congenital antithrombin deficiency

Characterization of molecular defect of 13387-9delG mutated antithrombin in inherited type I antithrombin deficiency

Two Novel Gene Mutations in Type I Antithrombin Deficiency

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