Homozygous intronic mutation leading to inefficient transcription combined with a novel frameshift mutation in F13A1 gene causes FXIII deficiency

Wang, Wei; Huang, Lan; Ma, Qinghua; Xiao, Deqian; Chen, Xiaodan; Yang, Zhigang; Wang, Xiaoying; Zhou, Keyuan; Li, Gang; Xiao, Man; Du, Guankui; Hao, Xinbao; Cai, Wei

doi:10.1038/jhg.2011.41

Cited by 9 publications

(4 citation statements)

References 16 publications

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“…Previously only five FXIIIB mutations, including only one missense mutation, were reported. To date, there have been several expression-based analytical studies for mutations associated with severe FXIII deficiency [Balogh et al, 2000;Hettasch and Greenberg, 1994;Maeda et al, 2012;Mikkola et al, 1997;Vysokovsky et al, 2006;Wang et al, 2011;Zheng et al, 2011]. However, only one of these investigated a FXI-IIB missense mutation that was at that time the only one known and that causes mild-to-moderate FXIII deficiency [Hashiguchi and Ichinose, 1995;Saito et al, 1990].…”

Section: Introductionmentioning

confidence: 99%

In VitroSecretion Deficits are Common Among Human Coagulation Factor XIII Subunit B Missense Mutants: Correlations with Patient Phenotypes and Molecular Models

Biswas¹,

Thomas²,

Bevans

et al. 2013

Human Mutation

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Coagulation factor XIII (FXIII) proenzyme circulates in plasma as a heterotetramer composed of two each of A and B subunits. Upon activation, the B subunits dissociate from the A subunit dimer, which gains transglutaminase activity to cross-link preformed fibrin clots increasing mechanical strength and resistance to degradation. The B subunits are thought to possess a carrier/protective function before FXIII activation. Mutations in either A or B subunits are associated with pathological patient phenotypes characterized by mild to severe bleeding. In vitro expression of FXIII B subunit (FXIIIB) missense variants in HEK293T cells revealed impaired secretion for all seven variants studied. To investigate the likely molecular environments of the missense residues, we created molecular models of individual FXIIIB Sushi domains using phylogenetically similar complement factor H Sushi domain structural templates. Assessment of the local molecular environments for the models suggested surface or buried positions for each mutant residue and possible pathological mechanisms. The in vitro expression system and in silico analytical methods and models we developed can be used to further investigate the molecular basis of FXIIIB mutation pathologies.

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Section: Introductionmentioning

confidence: 99%

In VitroSecretion Deficits are Common Among Human Coagulation Factor XIII Subunit B Missense Mutants: Correlations with Patient Phenotypes and Molecular Models

Biswas¹,

Thomas²,

Bevans

et al. 2013

Human Mutation

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“…Recently, a regulatory polymorphism intron 1 variant IVS1+12(A) was observed to influence the FXIII level using a reporter gene based expression assay (31). Later this polymorphism was found to be highly prevalent in patients with mild factor XIII deficiency (32).…”

Section: Val34leu Polymorphismmentioning

confidence: 99%

Coagulation factor XIII deficiency

Biswas¹,

Ivaškevičius²,

Thomas³

et al. 2014

Hamostaseologie

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SummaryThe plasma circulating zymogenic coagulation factor XIII (FXIII) is a protransglutaminase, which upon activation by thrombin and calcium cross-links preformed fibrin clots/fibrinolytic inhibitors making them mechanically stable and less susceptible to fibrinolysis. The zymogenic plasma FXIII molecule is a heterotetramer composed of two catalytic FXIII-A and two protective FXIII-B subunits. Factor XIII deficiency resulting from inherited or acquired causes can result in pathological bleeding episodes. A diverse spectrum of mutations have been reported in the F13A1 and F13B genes which cause inherited severe FXIII deficiency. The inherited severe FXIII deficiency, which is a rare coagulation disorder with a prevalence of 1 in 4 million has been the prime focus of clinical and genetic investigations owing to the severity of the bleeding phenotype associated with it. Recently however, with a growing understanding into the pleiotropic roles of FXIII, the fairly frequent milder form of FXIII deficiency caused by heterozygous mutations has become one of the subjects of investigative research. The acquired form of FXIII deficiency is usually caused by generation of autoantibodies or hyperconsumption in other disease states such as disseminated intravascular coagulation. Here, we update the knowledge about the pathophysiology of factor XIII deficiency and its therapeutic options.

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“…The F13A gene is located on chromosome 6p24-25 and contains 15 exons and 14 introns; it encodes a 731-amino acid protein which consists of five structural domains: an activation peptide (residues 1-37), β-sandwich (residues 38-183), catalytic core region (residues 184-515) which contains the catalytic triad of Cys314-His373-Asp396 [3], β-barrel 1 and 2 (residues 516-627 and residues 628-731, respectively) [4]. To date, 183 F13A gene mutations had been reported in The Human Gene Mutation Database (HGMD) with a high degree of ethnic heterogeneity; only four missense mutations [5][6][7], four nonsense mutations [6,8], three deletions [9,10] of them were detected among Chinese. The F13B gene, located on 1q31.3, encodes the B subunit of FXIII-B 2 , which likely act as carrier proteins.…”

Section: Introductionmentioning

confidence: 99%

Pathogenicity analysis of variations and prenatal diagnosis in a hereditary coagulation factor XIII deficiency family

et al. 2018

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Homozygous intronic mutation leading to inefficient transcription combined with a novel frameshift mutation in F13A1 gene causes FXIII deficiency

Cited by 9 publications

References 16 publications

In VitroSecretion Deficits are Common Among Human Coagulation Factor XIII Subunit B Missense Mutants: Correlations with Patient Phenotypes and Molecular Models

In VitroSecretion Deficits are Common Among Human Coagulation Factor XIII Subunit B Missense Mutants: Correlations with Patient Phenotypes and Molecular Models

Coagulation factor XIII deficiency

Pathogenicity analysis of variations and prenatal diagnosis in a hereditary coagulation factor XIII deficiency family

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