Impaired Cotranslational Processing as a Mechanism for Type I Antithrombin Deficiency

Fitches, Alison C.; Appleby, Ruth D.; Lane, David A.; Stefano, Valerio De; Leone, Giuseppe; Olds, R.J.

doi:10.1182/blood.v92.12.4671

Cited by 21 publications

(10 citation statements)

References 30 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 (13–19). Our patient maintained an innate half dose of functional antithrombin, and did not have a history of thrombosis from birth.…”

Section: Discussionsupporting

confidence: 51%

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: 51%

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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“…Disruption of the hydrophobic domain of the signal peptide may have impaired translocation into the endoplasmic reticulum and thus prevented cotranslational processing of preproSP-B. An analagous substitution in the hydrophobic core of the signal peptide of antithrombin prevented translocation into microsomes and post-translational glycosylation and resulted in antithrombin deficiency (25).…”

Section: Discussionmentioning

confidence: 99%

Allelic Heterogeneity in Hereditary Surfactant Protein B (SP-B) Deficiency

Nogee

Wert

Proffit

et al. 2000

Am J Respir Crit Care Med

225

176

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Inability to produce surfactant protein B (SP-B) causes fatal neonatal respiratory disease. A frame-shift mutation (121ins2) is the predominant but not exclusive cause of disease. To determine the range of mechanisms responsible for SP-B deficiency, both alleles from 32 affected infants were characterized. Sixteen infants were homozygous for the 121ins2 mutation, 10 infants were heterozygous for the 121ins2 and another mutation, and six infants were homozygous for other mutations. Thirteen novel SP-B gene mutations were identified, which were not found in a control population. One novel mutation was found in two unrelated families. Surfactant protein expression was evaluated by immunohistochemistry and/or protein blotting. Absence of proSP-B and mature SP-B was associated with nonsense and frame-shift mutations. In contrast, proSP-B expression was associated with missense mutations, or mutations causing in-frame deletions or insertions, and low levels of mature SP-B expression were associated with four mutations. Extracellular staining for proSP-C and/or aberrantly processed SP-C was observed in lungs of all infants with SP-B gene mutations. Hereditary SP-B deficiency is caused by a variety of distinct mutations in the SP-B gene and may be associated with reduced, as well as absent, levels of mature SP-B, likely caused by impaired processing of proSP-B.

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“…Missense mutations that result in quantitative deficiency have also been described. Thus, amino acid substitutions in the signal peptide that result in impaired cotranslational processing and quantitative deficiency of AT have been described (Fitches et al. , 1998).…”

Section: Molecular Genetic Analysis Of the Antithrombin Genementioning

confidence: 99%

The phenotypic and genetic assessment of antithrombin deficiency

Cooper¹,

Coath

Daly

et al. 2011

Int J Lab Hematology

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Summary Introduction: Antithrombin (AT) deficiency is associated with an increased risk of deep vein thrombosis and pulmonary embolism which are major causes of morbidity and death. The incidence of deficiency in healthy populations has been reported to vary from 1/600 to 1/5 000, with the variation being due to the different populations studied and detection methods used. When reduced activity levels are identified it is important to measure the AT antigen levels to differentiate type I from type II disorders, as type II defects have varying thrombotic risk. Methods: Functional AT assays detect the ability of AT to inactivate thrombin or factor Xa, and AT antigen assays detect the quantity of AT in plasma. In functional assays, reducing the incubation time of sample with enzyme/heparin reagent may increase sensitivity to type II defects. An excess of antigen over activity level suggests the presence of functionally defective AT, which can be characterized further by assaying AT in the absence of heparin, electrophoresis to investigate the ability of heparin to bind to AT, and gene sequencing. Results: Many patients with AT deficiency have a type II defect and these defects may not be detected by all routine diagnostic assays. Assays using human thrombin may lack specificity and assays that use factor Xa may fail to detect the common variant, AT Cambridge II, which can be detected by assays using bovine thrombin, especially if activity is compared to antigen by ratio. Factor Xa based assays may be particularly sensitive to certain heparin binding defects, and sensitivity of assays to both heparin binding and reactive site defects can be improved by shortening the incubation time with enzyme. Conclusion: AT activity assays are essential for the detection of AT deficiency because type II defects are relatively common in patients with heritable deficiency. No one functional assay can be assumed to detect all forms of AT deficiency, and assays can sometimes be improved by reducing reaction time of AT with thrombin or factor Xa.

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Impaired Cotranslational Processing as a Mechanism for Type I Antithrombin Deficiency

Cited by 21 publications

References 30 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

Allelic Heterogeneity in Hereditary Surfactant Protein B (SP-B) Deficiency

The phenotypic and genetic assessment of antithrombin deficiency

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