scholarly journals Type I factor XIII deficiency is caused by a genetic defect of its b subunit: insertion of triplet AAC in exon III leads to premature termination in the second Sushi domain

Blood ◽  
1996 ◽  
Vol 87 (7) ◽  
pp. 2769-2774 ◽  
Author(s):  
T Izumi ◽  
T Hashiguchi ◽  
G Castaman ◽  
A Tosetto ◽  
F Rodeghiero ◽  
...  
Keyword(s):  
Factor Xiii ◽  
Stop Codon ◽  
Genetic Defect ◽  
Type I ◽  
Type Ii ◽  
Factor Xiii Deficiency ◽  
B Subunit ◽  
I Factor ◽  
A Subunit ◽  
Nucleotide Triplet

Factor XIII deficiency has been classified into two categories: type I deficiency, characterized by the lack of both the a and b subunits; and type II deficiency, characterized by the lack of the a subunit alone. To clarify the genetic bases of these diseases, previously reported cases of the type I deficiency were examined at the DNA level. DNA sequence analysis showed that a nucleotide triplet (AAC) was inserted within the codon for Tyr-80 in exon III of the gene for a female proband's b subunit, resulting in the creation of a stop codon. Restriction digestion of amplified DNAs confirmed that the proband and her sister were homozygotes, and their family members were heterozygotes of this mutant allele. A truncated protein composed of 79 amino acids could be synthesized by these homozygotes; however, such a protein would not be secreted or it would degrade quickly, because there were normal amounts of the mutant mRNA, but no b subunit was detected in these patients. The a subunit deficiency of these patients must be a secondary to the b subunit deficiency, as their gene for the a subunit was intact, and the a subunit in their platelets was present within normal levels.

Clinical pharmacokinetics of a placenta-derived factor XIII concentrate in type I and type II factor XIII deficiency

1991 ◽  
Vol 36 (1) ◽  
pp. 30-34 ◽  
Author(s):  
Francesco Rodeghiero ◽  
Alberto Tosetto ◽  
Eros Di Bona ◽  
Giancarlo Castaman
Keyword(s):  
Factor Xiii ◽  
Type I ◽  
Type Ii ◽  
Factor Xiii Deficiency ◽  
Clinical Pharmacokinetics

Type I and type II disease in congenital factor XIII deficiency

1986 ◽  
Vol 53 (5) ◽  
pp. 411-413 ◽  
Author(s):  
A. Girolami ◽  
M. G. Cappellato ◽  
A. R. Lazzaro ◽  
M. Boscaro
Keyword(s):  
Factor Xiii ◽  
Type I ◽  
Type Ii ◽  
Factor Xiii Deficiency ◽  
Congenital Factor

Physiopathology and Regulation of Factor XIII

2001 ◽  
Vol 86 (07) ◽  
pp. 57-65 ◽  
Author(s):  
Akitada Ichinose
Keyword(s):  
Factor Xiii ◽  
Mrna Level ◽  
Factor Xiii Deficiency ◽  
Specific Expression ◽  
Nonsense Mutations ◽  
B Subunit ◽  
Cell Type Specific Expression ◽  
A Subunit ◽  
Cell Type Specific ◽  
Substrate Proteins

SummaryFactor XIII is a plasma transglutaminase. Transglutaminases are at least 8 enzymes which cross-link a number of proteins. This type of reaction not only enhances the original functions of substrate proteins, but also adds new functions to them. Factor XIII in plasma is a tetramer (A2B2), and the A subunit contains the active site. Although transglutaminases are homologous, the nucleotide sequences in their 5’-flanking region differ significantly. Accordingly, transcription factors play a major role in the cell type-specific expression of each transglutaminase. A variety of missense and nonsense mutations, and deletions/insertions with or without out-of-frame shift/premature termination and splicing abnormalities have been identified in the genes for A and B subunits in factor XIII deficiency. In some cases, the mRNA level of the A or B subunit was severely reduced. Molecular and cellular bases have also been explored by expression experiments and by molecular modeling. In most cases, impaired folding and/or conformational change of the mutant A or B subunit leads to both intra- and extra-cellular instability, which is responsible for factor XIII deficiency.

Truncated mutant B subunit for factor XIII causes its deficiency due to impaired intracellular transportation

Blood ◽  
2001 ◽  
Vol 97 (9) ◽  
pp. 2667-2672 ◽  
Author(s):  
Shiori Koseki ◽  
Masayoshi Souri ◽  
Shinichiro Koga ◽  
Mitsunori Yamakawa ◽  
Tsutomu Shichishima ◽  
...  
Keyword(s):  
Factor Xiii ◽  
Novel Mutation ◽  
Japanese Patients ◽  
Type I ◽  
B Subunit ◽  
Expression Studies ◽  
I Factor ◽  
Electron Microscopes ◽  
Cellular Pathology

Abstract Two Japanese patients were newly diagnosed as having B subunit (XIIIB) deficiency of factor XIII (former type I deficiency). Both patients have a previously described one-base deletion at the boundary between intron A/exon II in the XIIIB gene, heterozygously or homozygously. A founder effect was proposed for this mutation because 3 unrelated patients with XIIIB deficiency also share 2 3′-polymorphisms. In one patient heterozygous for the above mutation, a novel mutation was also identified: a deletion of guanosine in exon IX (delG) of the XIIIB gene. To understand the molecular and cellular pathology of the delG mutation, expression studies were performed using a cultured mammalian cell line. Pulse-chase experiments showed that a resultant truncated XIIIB remained inside the cells and could not be secreted into the culture medium. Furthermore, immunocytochemical examinations by epifluorescence, confocal, and electron microscopes indicated impaired intracellular transportation of the truncated XIIIB from the endoplasmic reticulum to the Golgi apparatus. No mutations in the gene for the A subunit (XIIIA) were identified in this patient. Therefore, secretion of the truncated XIIIB must also be impaired in vivo, leading to a secondary XIIIA deficiency. These results support a previous conclusion that genetic defects of XIIIB are the basis for the former type I factor XIII deficiency.

CONGENITAL FACTOR XIII DEFICIENCY: TYPE I AND TYPE II DISEASE

1985 ◽  
Vol 60 (2) ◽  
pp. 375-376 ◽  
Author(s):  
Antonio Girolami ◽  
Maria Giovanna Cappellato ◽  
Maria Angela Vicarioto
Keyword(s):  
Factor Xiii ◽  
Type I ◽  
Type Ii ◽  
Factor Xiii Deficiency ◽  
Deficiency Type ◽  
Congenital Factor

Detection And Regulation Of The Subunit Proteins Of Plasma Factor XIII

1981 ◽  
Author(s):  
J McDonagh ◽  
C Skrzynia ◽  
S Ikematsu
Keyword(s):  
Factor Xiii ◽  
Protein A ◽  
Carrier Protein ◽  
Variable Amount ◽  
Factor Xiii Deficiency ◽  
B Subunit ◽  
Catalytic Function ◽  
Normal Plasma ◽  
Plasma Factor ◽  
A Subunit

Plasma factor XIII circulates as a noncovalently-associated, tetrameric zymogen (a2b2). The a subunit has the potential catalytic function, while the b subunit may act as a carrier protein plasma. In order to study the interactions between the two subunits, specific radioimmunoassays have been developed for each subunit. The assays are valid for measuring a and b protein concentrations in plasma and serum as well as in purified systems. The a assay detects all forms of the protein (zymogen, intermediate, enzyme). Factor XIII activity was measured by the monodansylcadaverine assay. These methods were used to correlate a and b protein concentrations with factor XIII activity in normal donors, in patients with factor XIII deficiency and their family members, and in patients with factor XIII inhibitors.The normal plasma concentration of each of the subunits of factor XIII is about 12 μg/ml, making the concentration of the zymogen complex to be 0.15 μM. All of the b protein is recovered in serum, while a variable amount of a protein (a*) is found in serum. a protein and factor XIII activity go in parallel in normal, factor XIII deficient, and heterozygous plasma samples. Deficient patients have <1% activity and <20 ng/ml a protein. Deficient patients have about 50% of the normal plasma b concentration, and heterozygotes have 50% a and 75% b protein. In three cases of spontaneous, autoimmune inhibitors against factor XIII, there was no detectable activity and b concentration was one-half normal. Following transfusion of two factor XIII deficient patients with a subunit, activity rose immediately to the expected levels, while b rose more slowly to 20% above the preinfusion level. All of these studies indicate that the circulating level of functional a subunit exerts a positive feedback effect on the concentration of b subunit in plasma.

scholarly journals Molecular Mechanisms of Type II Factor XIII Deficiency: Novel Gly562-Arg Mutation and C-Terminal Truncation of the A Subunit Cause Factor XIII Deficiency as Characterized in a Mammalian Expression System

Blood ◽  
1998 ◽  
Vol 91 (8) ◽  
pp. 2830-2838 ◽  
Author(s):  
Nobumasa Takahashi ◽  
Hiroaki Tsukamoto ◽  
Hideaki Umeyama ◽  
Giancarlo Castaman ◽  
Francesco Rodeghiero ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Factor Xiii ◽  
Molecular Mechanisms ◽  
Expression System ◽  
Nucleotide Sequence Analysis ◽  
Type Ii ◽  
Factor Xiii Deficiency ◽  
Mammalian Expression ◽  
Mammalian Expression System ◽  
A Subunit

To explore the biological and clinical implications of the structure/function relationships in factor XIII, mutations in two patients with type II deficiency were identified and characterized in a mammalian expression system. Nucleotide sequence analysis of the A subunit gene showed that case no. 1 had a deletion of 4 bp (AATT) in exon XI and that, in case no. 2, Gly562 (GGG) had been replaced by Arg(AGG). The deletion in case no. 1 leads to a premature termination at codon 464. Restriction digestion of amplified DNAs confirmed that both cases were homozygous for their respective mutations. Reverse transcription-polymerase chain reaction analysis demonstrated that the level of mRNA was greatly reduced in case no. 1, whereas the level of mutant mRNA expressed in case no. 2 was normal. Molecular modeling calculated that Arg562 changed the conformation of the A subunit, suggesting misfolding and/or destabilization of the molecule. To determine how these mutations impaired synthesis of the A subunit, recombinant A subunits bearing the mutations were expressed in mammalian cells. Pulse-chase experiments showed that the mutants were synthesized normally but disappeared rapidly, whereas the wild-type remained. These results indicate that both mutant proteins with an altered conformation become prone to rapid degradation, resulting in factor XIII deficiency in these patients.

scholarly journals Biochemical and structural characterization of the novel sialic acid-binding site of Escherichia coli heat-labile enterotoxin LT-IIb

2016 ◽  
Vol 473 (21) ◽  
pp. 3923-3936 ◽  
Author(s):  
Dani Zalem ◽  
João P. Ribeiro ◽  
Annabelle Varrot ◽  
Michael Lebens ◽  
Anne Imberty ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Binding Site ◽  
Cholera Toxin ◽  
Carbohydrate Binding ◽  
Type I ◽  
Type Ii ◽  
E Coli ◽  
B Subunit ◽  
Heat Labile ◽  
B Subunits

The structurally related AB5-type heat-labile enterotoxins of Escherichia coli and Vibrio cholerae are classified into two major types. The type I group includes cholera toxin (CT) and E. coli LT-I, whereas the type II subfamily comprises LT-IIa, LT-IIb and LT-IIc. The carbohydrate-binding specificities of LT-IIa, LT-IIb and LT-IIc are distinctive from those of cholera toxin and E. coli LT-I. Whereas CT and LT-I bind primarily to the GM1 ganglioside, LT-IIa binds to gangliosides GD1a, GD1b and GM1, LT-IIb binds to the GD1a and GT1b gangliosides, and LT-IIc binds to GM1, GM2, GM3 and GD1a. These previous studies of the binding properties of type II B-subunits have been focused on ganglio core chain gangliosides. To further define the carbohydrate binding specificity of LT-IIb B-subunits, we have investigated its binding to a collection of gangliosides and non-acid glycosphingolipids with different core chains. A high-affinity binding of LT-IIb B-subunits to gangliosides with a neolacto core chain, such as Neu5Gcα3- and Neu5Acα3-neolactohexaosylceramide, and Neu5Gcα3- and Neu5Acα3-neolactooctaosylceramide was detected. An LT-IIb-binding ganglioside was isolated from human small intestine and characterized as Neu5Acα3-neolactohexaosylceramide. The crystal structure of the B-subunit of LT-IIb with the pentasaccharide moiety of Neu5Acα3-neolactotetraosylceramide (Neu5Ac-nLT: Neu5Acα3Galβ4GlcNAcβ3Galβ4Glc) was determined providing the first information for a sialic-binding site in this subfamily, with clear differences from that of CT and LT-I.

The Molecular Basis of Antithrombin Deficiency in Belgian and Dutch Families

1998 ◽  
Vol 80 (09) ◽  
pp. 376-381 ◽  
Author(s):  
W. Lissens ◽  
S. Seneca ◽  
P. Capel ◽  
B. Chatelain ◽  
P. Meeus ◽  
...  
Keyword(s):  
Molecular Basis ◽  
Gene Deletion ◽  
Direct Sequencing ◽  
Genetic Defect ◽  
Polymorphism Analysis ◽  
Type I ◽  
Type Ii ◽  
Antithrombin Deficiency ◽  
Venous Thromboembolic Events ◽  
At Deficiency

SummaryThe molecular basis of hereditary antithrombin (AT) deficiency has been investigated in ten Belgian and three Dutch unrelated kindreds. Eleven of these families had a quantitative or type I AT deficiency, with a history of major venous thromboembolic events in different affected members. In the other two families a qualitative or type II AT deficiency was occasionally diagnosed.DNA studies of the AT gene were performed, using polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) analysis, followed by direct sequencing of the seven exons and intronexon junction regions. Six novel point mutations were identified: four missense, one nonsense mutation and a single nucleotide deletion near the reactive site, causing a frameshift with premature translation termination. In two kindreds the underlying genetic defect was caused by a whole gene deletion, known as a rare cause of AT deficiency. In these cases, Southern blot and polymorphism analysis of different parts of the AT gene proved useful for diagnosis. In another kindred a partial gene deletion spanning 698 basepairs could precisely be determined to a part of intron 3B and exon 4. In two type I and in both type II AT deficient families a previously reported mutation was identified. In all cases, the affected individuals were heterozygous for the genetic defect.

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