A Founder Effect Is Proposed for Factor XIII B Subunit Deficiency Caused by the Insertion of Triplet AAC in Exon III Encoding the Second Sushi Domain

Souri, Masayoshi; Izumi, Taisuke; Higashi, Yuji; Girolami, Antonio; Ichinose, Akitada

doi:10.1055/s-0037-1615173

Cited by 20 publications

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References 45 publications

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“…More than 200 cases of FXIII deficiency have been identified, most of which cases were found to be caused by mutations in the FXIII-A gene resulting in the lack of FXIII-A alone [16,17]. On the other hand, only five cases of FXIII-B deficiency have been published at this point [18][19][20][21]. In patients with FXIII-B deficiency, FXIII-B is completely lost and FXIII-A significantly decreases to 5-40% of normal in plasma, although a normal amount of FXIII-A exists in platelets [19,21,22], suggesting a protective effect of FXIII-B on plasma FXIII-A.…”

Section: Introductionmentioning

confidence: 99%

Administration of factor XIII B subunit increased plasma factor XIII A subunit levels in factor XIII B subunit knock-out mice

et al. 2007

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Factor XIII (FXIII) is a proenzyme of plasma transglutaminase consisting of enzymatic A (FXIII-A) and noncatalytic B subunits (FXIII-B), and acts in hemostasis and wound healing. We freshly generated mice lacking either FXIII-A or FXIII-B to investigate the physiological functions of FXIII in vivo. Mice carrying the disrupted allele were born at the expected Mendelian ratios, and the homozygous mice were viable and fertile under specific pathogen-free conditions. Although all homozygous and heterozygous mice showed no marked difference from the wild-type animals in general appearance, homozygous mice of either FXIII-A- or FXIII-B-deficiency did have prolonged bleeding times. It was confirmed that thrombin-dependent amine incorporation and fibrin-crosslinking in plasma were undetectable in the FXIII-A-deficient mice and markedly reduced in the FXIII-B-deficient mice; however, the gene expression of each subunit was regulated independently. Recombinant human FXIII-B (rFXIII-B) was expressed in a baculovirus expression system. When rFXIII-B was injected into FXIII-B-deficient mice, FXIII-A levels, fibrin crosslinking, and amine-incorporation activities increased in their plasma, indicating that FXIII-B assisted the maintenance of FXIII-A levels in the circulation. These mouse strains will be useful in exploring the possible pathophysiological roles of each subunit in vivo.

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Section: Introductionmentioning

confidence: 99%

Administration of factor XIII B subunit increased plasma factor XIII A subunit levels in factor XIII B subunit knock-out mice

et al. 2007

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“…[3][4][5] To understand the molecular pathology of these deficiencies, we have identified a number of mutations in the F13A and F13B genes in patients' DNA and have analyzed the molecular mechanisms of FXIII deficiency using in vitro procedures. [6][7][8][9][10][11][12][13][14][15] Because it is not possible to understand completely the clinical pathologic mechanisms of this disease in vivo, we performed functional analyses on FXIIIA knockout (KO) mice.…”

Section: Introductionmentioning

confidence: 99%

Factor XIII A subunit-deficient mice developed severe uterine bleeding events and subsequent spontaneous miscarriages

Koseki-Kuno

Yamakawa

Dickneite

et al. 2003

Blood

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IntroductionCoagulation factor XIII (FXIII) is a heterotetramer consisting of A subunits (FXIIIA) and B subunits (FXIIIB). FXIII catalyzes intermolecular cross-linking reactions between fibrin monomers, ␣ 2 -plasmin inhibitor, and fibronectin. These reactions increase the mechanical strength of the fibrin clot and its resistance to proteolytic degradation and enhance the assembly of the extracellular matrix. Accordingly, a deficiency of FXIII results in defective cross-linking reactions of these substrates and is thus associated with a number of diseases. 1 Congenital FXIII deficiency is caused by defects in the F13A or F13B genes, 2 leading to a bleeding tendency and abnormal wound healing in affected patients and spontaneous miscarriage in female patients. [3][4][5] To understand the molecular pathology of these deficiencies, we have identified a number of mutations in the F13A and F13B genes in patients' DNA and have analyzed the molecular mechanisms of FXIII deficiency using in vitro procedures. 6-15 Because it is not possible to understand completely the clinical pathologic mechanisms of this disease in vivo, we performed functional analyses on FXIIIA knockout (KO) mice. Study designFXIIIA KO mice were created by replacing exon VII with a neomycinresistance cassette as described previously. 16 All KO and wild-type CBA mice were housed in a specific pathogen-free facility. Experimental procedures were approved by the Animal Care and Use Committee of Yamagata University and were carried out in accordance with the guidelines of this committee and that of Japanese governmental law.Using tail biopsy DNA, genotyping of the mice was performed by polymerase chain reaction (PCR) with 2 forward primers designed from the neomycin-resistant gene (5Ј-CAC TGC ATT CTA GTT GTG GTT TGT CC-3Ј) and exon VII of the mouse F13A gene (5Ј-GCC AAG GAT GAT GAA GGT GTT CTT-3Ј), respectively, and a common reverse primer from intron G (5Ј-CCC TGA GAC TTA CGG ATG AAG AAG-3Ј).Tissues collected for histologic analyses were placed in 10% neutralbuffered formalin, processed into paraffin, and 3-m sections were prepared and stained with hematoxylin and eosin by standard techniques.The distribution of events between the study groups was analyzed using 4 ϫ 2 contingency tables for individual study groups as well as 2 ϫ 2 tables for a combined group of female wild-type mice and female homozygous FXIIIA KO mice. The 2 test was also carried out by using StatView software (Abacus Concepts, Berkeley, CA). Differences were considered statistically significant at P values less than .05. Results and discussionWestern blot analysis and amine-incorporation enzymatic assay confirmed the complete absence of FXIIIA in the uterus and plasma (where FXIIIA is normally expressed/present) of the homozygous FXIIIA KO mice identified by genotyping (data not shown). Despite the complete loss of FXIIIA, all homozygous FXIIIA KO mice had appeared normal at birth as previously reported. 16 Whereas all 20 of the female homozygous KO mice survived, 3 of 20 male KO mice...

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“…Patients 2 and 3 were unrelated and a founder effect was proposed for XIIIB deficiency among the Italians. 12 In the present study, 2 Japanese patients were newly diagnosed as having XIIIB deficiency. Both were found to be heterozygous or homozygous for the known agϪ(Ϫ)g mutation.…”

Section: Introductionmentioning

confidence: 82%

“…We previously proposed a founder effect for XIIIB deficiency in Italians, which is caused by an AAC insertion. 12 Similarly, a founder effect is now proposed for XIIIB deficiency in Japanese, which is caused by the agϪ(Ϫ)g mutation.…”

Section: Discussionmentioning

confidence: 99%

“…9,11,12 For detection of a novel mutation (delG), an oligonucleotide with one base mismatch (in italic) was designed as an antisense primer, 5Ј-CTC TGT TGC ACT GCA CAG AGA ATT-3Ј (E9Gdel). A fragment containing exon IX was amplified by a combination of E9Gdel and a sense primer, 5Ј-ATA AAG CTT TTG AAA CTT GTC ATA ATT TTT GTT TTA-3Ј (B4-5H).…”

Section: Screening For Mutations In the Xiiib Gene By Pcr-restrictionmentioning

confidence: 99%

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

Koseki

Souri

Koga

et al. 2001

Blood

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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. Pulsechase 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. (Blood. 2001;97:2667-2672)

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A Founder Effect Is Proposed for Factor XIII B Subunit Deficiency Caused by the Insertion of Triplet AAC in Exon III Encoding the Second Sushi Domain

Cited by 20 publications

References 45 publications

Administration of factor XIII B subunit increased plasma factor XIII A subunit levels in factor XIII B subunit knock-out mice

Administration of factor XIII B subunit increased plasma factor XIII A subunit levels in factor XIII B subunit knock-out mice

Factor XIII A subunit-deficient mice developed severe uterine bleeding events and subsequent spontaneous miscarriages

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

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