An update of the mutation profile of Factor 13 A and B genes

Biswas, Arijit; Ivaškevičius, Vytautas; Seitz, Rainer; Thomas, Anne; Oldenburg, Johannes

doi:10.1016/j.blre.2011.03.001

Cited by 44 publications

(54 citation statements)

References 75 publications

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“…In blood plasma, Factor XIII exists as a heterotetramer composed of two catalytic subunits (Factor XIII A) and two inhibitory subunits (Factor XIII B). 27 This study showed that the expression of Factor XIII B was increased in gastric cancer with lymph node metastasis and its level correlated with lymph node metastasis. The increased expression of Factor XIII B was also observed in several cancer cell lines, including RT4, UICC3, T24, T24t, MDA-MD 231, HeLa, H1975 and K562 (data not show), suggesting that these tumor cells produce this protein.…”

Section: Discussionmentioning

confidence: 82%

Protein predictive signatures for lymph node metastasis of gastric cancer

Wang

et al. 2012

Intl Journal of Cancer

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Lymph node status remains one of most crucial indicators of gastric cancer prognosis and treatment planning. Current imaging methods have limited accuracy in predicting lymph node metastasis. We sought to identify protein markers in primary gastric cancer and to define a risk model to predict lymph node metastasis. The Protein Pathway Array (PPA) (initial selection) and Western blot (confirmation) were used to assess the protein expression in a total of 190 freshly frozen gastric cancer samples. The protein expression levels were compared between samples with lymph node metastasis (n 5 73) and those without lymph node metastasis (n 5 57) using PPA. There were 27 proteins differentially expressed between lymph node positive samples and lymph node negative samples. Five proteins (Factor XIII B, TFIIH p89, ADAM8, COX-2 and CUL-1) were identified as independent predictors of lymph node metastasis. Together with vascular/lymphatic invasion status, a risk score model was established to determine the risk of lymph node metastasis for each individual gastric cancer patient. The ability of this model to predict lymph node metastasis was further confirmed in a second cohort of gastric cancer patients (33 with and 27 without lymph node metastasis) using Western blot. This study indicated that some proteins differentially expressed in gastric cancer can be selected as clinically useful biomarkers. The risk score model is useful for determining patients' risk of lymph node metastasis and prognosis.Gastric cancer is the fourth most common malignancy and the second leading cause of cancer-related death, after lung cancer, in the world. More than 80% of patients are diagnosed at an advanced stage or experienced tumor recurrence after surgical resection.1 Despite of some decline in the incidence and prolonged overall survival of gastric cancer patients in the past decade thanks to the advancement of treatments (e.g., surgery, chemotherapy and radiotherapy), gastric cancer continues to be a major health problem with a high mortality rate. 2Most gastric cancer patients are diagnosed at Stages III or IV, with 50-75% of patients presenting with lymph node metastasis.3 The preoperative determination of lymph node status is critical in tumor staging and in planning optimal management of gastric cancer patients. For early gastric cancer without lymph node involvement, less invasive treatment (e.g., endoscopic mucosal resection) can be performed. For localized gastric cancer without lymph node involvement, surgical resection with limited lymph node dissection is recommended to reduce postoperative morbidity and mortality. For advanced gastric cancer with lymph node involvement, surgical resection with extensive lymphadenectomy is necessary to achieve better outcome. 4 Currently, preoperative assessment of lymph node status is mainly based on imaging studies such as computerized tomography, magnetic resonance imaging and positron emission tomography/computed tomography. However, many studies show that lymph node size determined by imagin...

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Section: Discussionmentioning

confidence: 82%

Protein predictive signatures for lymph node metastasis of gastric cancer

Wang

et al. 2012

Intl Journal of Cancer

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“…At least 37 missense mutations with a phenotype have been reported to date, most of which are predicted to destabilize the protein. 86,87 The affected residues are mapped onto the structure in Figure 7.…”

Section: 38mentioning

confidence: 99%

Regulation of the activities of the mammalian transglutaminase family of enzymes

Klöck

Khosla

2012

Protein Science

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Mammalian transglutaminases catalyze post-translational modifications of glutamine residues on proteins and peptides through transamidation or deamidation reactions. Their catalytic mechanism resembles that of cysteine proteases. In virtually every case, their enzymatic activity is modulated by elaborate strategies including controlled gene expression, allostery, covalent modification, and proteolysis. In this review, we focus on our current knowledge of posttranslational regulation of transglutaminase activity by physiological as well as synthetic allosteric agents. Our discussion will primarily focus on transglutaminase 2, but will also compare and contrast its regulation with Factor XIIIa as well as transglutaminases 1 and 3. Potential structure-function relationships of known mutations in human transglutaminases are analyzed.

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“…While the homozygous inherited form of this deficiency caused by FXIIIA (OMIM #613225) or FXIIIB (OMIM #613235) gene mutations is rare (1 in 4–6 million), the milder heterozygous form is more frequent (Biswas et al. 2011; Biswas et al. 2014a,b).…”

Section: Introductionmentioning

confidence: 99%

Structural and functional influences of coagulation factor XIII subunit B heterozygous missense mutants

Thomas¹,

Biswas²,

Ivaškevičius³

et al. 2015

Molec Gen & Gen Med

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The coagulation factor XIII(FXIII) is a plasma circulating heterotetrameric protransglutaminase that acts at the end of the coagulation cascade by covalently cross-linking preformed fibrin clots (to themselves and to fibrinolytic inhibitors) in order to stabilize them against fibrinolysis. It circulates in the plasma as a heterotetramer composed of two homomeric catalytic Factor XIIIA2 (FXIIIA2) and two homomeric protective/carrier Factor XIIIB2 subunit (FXIIIB2). Congenital deficiency of FXIII is of two types: severe homozygous/compound heterozygous FXIII deficiency which results in severe bleeding symptoms and mild heterozygous FXIII deficiency which is associated with mild bleeding (only upon trauma) or an asymptomatic phenotype. Defects in the F13B gene (Factor XIIIB subunit) occur more frequently in mild FXIII deficiency patients than in severe FXIII deficiency. We had recently reported secretion-related defects for seven previously reported F13B missense mutations. In the present study we further analyze the underlying molecular pathological mechanisms as well as the heterozygous expression phenotype for these mutations using a combination of in vitro heterologous expression (in HEK293T cells) and confocal microscopy. In combination with the in vitro work we have also performed an in silico solvated molecular dynamic simulation study on previously reported FXIIIB subunit sushi domain homology models in order to predict the putative structure-functional impact of these mutations. We were able to categorize the mutations into the following functional groups that: (1) affect antigenic stability as well as binding to FXIIIA subunit, that is, Cys5Arg, Cys316Phe, and Pro428Ser (2) affect binding to FXIIIA subunit with little or no influence on antigenic stability, that is, Ile81Asn and Val401Gln c) influence neither aspects and are most likely causality linked polymorphisms or functional polymorphisms, that is, Leu116Phe and Val217Ile. The Cys5Arg mutation was the only mutation to show a direct secretion-based defect since the mutated protein was observed to accumulate in the endoplasmic reticulum.

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An update of the mutation profile of Factor 13 A and B genes

Cited by 44 publications

References 75 publications

Protein predictive signatures for lymph node metastasis of gastric cancer

Protein predictive signatures for lymph node metastasis of gastric cancer

Regulation of the activities of the mammalian transglutaminase family of enzymes

Structural and functional influences of coagulation factor XIII subunit B heterozygous missense mutants

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