Alternative titles; symbols
HGNC Approved Gene Symbol: F13B
Cytogenetic location: 1q31.3 Genomic coordinates (GRCh38): 1:197,038,741-197,067,260 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q31.3 | Factor XIIIB deficiency | 613235 | Autosomal recessive | 3 |
The F13B gene encodes the B subunit of factor XIII (EC 2.3.2.13), the last enzyme generated in the blood coagulation cascade. It is the zymogen for fibrinoligase, a transglutaminase that forms intramolecular gamma-glutamyl-epsilon-lysine crosslinking between fibrin molecules and thus stabilizes blood clots. Plasma factor XIII is composed of 2 A subunits (F13A1; 134570), which have catalytic function, and 2 noncatalyic B subunits (F13B), which likely act as carriers proteins. Factor XIII is proteolytically activated by thrombin (F2; 176930) (Takahashi et al., 1986). (An earlier nomenclature for the 2 subunits was A for 'activity' and S for 'support'; B is now substituted for S.)
Ichinose et al. (1986) isolated clones corresponding to the beta-subunit of F13 from a human liver cDNA library. The deduced mature 641-residue protein contains 10 repetitive homologous segments, each composed of about 60 amino acids and 4 half-cysteine residues. These repeated segments belong to a family of repeats present in complement factor B (CFB; 138470) and haptoglobin alpha-1 (140100). Three potential Asn-linked carbohydrate attachment sites were also identified in the F13 beta subunit.
Grundmann et al. (1990) isolated clones corresponding to the human beta-subunit of factor XIII from a human liver cDNA library, and determined that the deduced 661-residue protein has a molecular mass of 75.5 kD.
Nonaka et al. (1993) isolated a full-length cDNA clone of mouse F13b and determined its entire sequence. The predicted amino acid sequence showed 77.5% homology with the human protein.
Leppert et al. (1987) demonstrated linkage of the F13B gene, defined by protein polymorphism, to 2 DNA markers on chromosome 1q: pMLAJ1 and EKH7.4. A VNTR (variable number tandem repeat) polymorphism located about 16 cM distal to Duffy (110700) showed a maximum lod score of 6.00 at theta = 0.217; EKH7.4, a TaqI RFLP located about 20 cM proximal to the REN locus (179820), showed a maximum lod score of 18.69 at theta = 0.088. These results indicated that F13B is located somewhere between 1q12 and 1q32.3, and is more closely situated to the latter band.
By in situ hybridization, Webb et al. (1989) assigned F13B to 1q31-q32.1 and perhaps more precisely to subband 1q31.2 or 1q31.3.
Rodriguez de Cordoba et al. (1988) found that F13B is closely linked to complement factor H (134370); the maximum lod score was 3.91 at a recombination fraction of 0.0. As pointed out by Hing et al. (1988), the linkage between the factor H and F13B genes (Eiberg et al., 1987) is of interest because of the structural homology between F13B and the RCA (regulator of complement activation) cluster of proteins, to which HF belongs.
By in situ hybridization and linkage studies in interspecific backcross mice, Nonaka et al. (1993) mapped the F13B gene to the distal portion of mouse chromosome 1, closely linked to Cfh. Structural similarity between F13b and Cfh, as well as the chromosomal proximity, indicated a close evolutionary relationship of the 2 genes.
Board (1980) used electrophoresis followed by immunofixation with a specific antiserum to describe genetic variation at the FXIII-beta locus. The locus was shown to be autosomal and to have 3 alleles, with a frequency in Australian blood donors of 0.747, 0.084, and 0.169. Using agarose gel isoelectric focusing followed by immunofixation, Kera et al. (1981) also described polymorphism of the B subunit. The allele frequencies in Japanese were 0.336 for the 'fast' gene and 0.664 for the 'slow' gene. Kamboh and Ferrell (1986) used isoelectric focusing followed by immunoblotting to study the polymorphism of factor XIIIB. Synthesis of the published data with their new data demonstrated remarkable variation in the distribution of the 3 common alleles at this locus and established it as a highly informative marker for population differentiation and evolutionary studies. Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988).
In a 32-year-old woman with factor XIII deficiency and complete absence of the B subunit of factor XIII (613235), (Saito et al., 1990), Hashiguchi et al. (1993) found compound heterozygosity for 2 mutations in the F13B gene (134580.0001 and 134580.0002).
A hint of linkage between F13B and cystic fibrosis (219700) was found by Eiberg et al. (1985). Bender et al. (1987) thought they could exclude F13B from chromosome 1p.
In a 32-year-old woman with factor XIII deficiency and complete absence of the B subunit of factor XIII (613235) (Saito et al., 1990), Hashiguchi et al. (1993) found compound heterozygosity for 2 mutations in the F13B gene. One of the alleles showed a 1-bp deletion of adenosine-4161 at the acceptor splice junction of intron A/exon 2, resulting in a loss of the obligatory AG splicing sequence. The absence of adenosine-4161 was confirmed by cleavage with TaqI endonuclease of the amplified DNAs. The other allele was a G-to-T transversion in exon 7, resulting in a cys430-to-phe (C430F; 134580.0002) substitution. The C430F mutation resulted in elimination of a disulfide bond in the seventh Sushi domain. This mutation could be confirmed by cleavage with MboII endonuclease.
Koseki et al. (2001) identified homozygosity for this mutation in a Japanese patient with F13B deficiency who showed umbilical bleeding. Another unrelated Japanese patient was compound heterozygous for this mutation and for a novel mutation in the F13B gene (134580.0005). Haplotype analysis of the IVS1AS mutation suggested a founder effect.
For discussion of the cys430-to-phe (C430F) mutation in the F13B gene that was found in compound heterozygous state in a patient with factor XIII deficiency and complete absence of the B subunit of factor XIII (613235) by Hashiguchi et al. (1993), see 134580.0001.
Komanasin et al. (2005) identified an 8259A-G transition in exon 3 of the F13B gene, resulting in a his95-to-arg (H95R) substitution in the second Sushi domain, as a polymorphism in Caucasian blood donors. Functional assays in plasma showed that the H95R substitution resulted in faster dissociation between the F13 alpha and beta subunits after activation by thrombin. However, in vitro studies of the purified variants showed no difference. The his/arg genotype was more frequent than the arg/age genotype in 214 Caucasian patients with venous thrombosis (see 188050) and 291 controls (22.4% vs 15.1%). The findings were replicated in a second cohort of 471 patients and 472 controls (18.5% vs 14.0%), yielding a pooled odds ratio (OR) of 1.5. The findings suggested that the arg95 variant is associated with a moderately increased risk for venous thrombosis.
Reiner et al. (2003) hypothesized that possession of either of 2 functional factor XIII polymorphisms: val34-to-leu (V34L; 134570.0010) within subunit A or his95-to-arg within subunit B, might modulate the prothrombotic effects of estrogen and help explain the variation in incidence of arterial thrombotic events among postmenopausal women using hormone replacement therapy. In a population-based case-control study of 955 postmenopausal women, they assessed the associations of factor XIII genotypes and their interactions with estrogen therapy on risk of nonfatal myocardial infarction (MI). The presence of the subunit A leu34 allele was associated with a reduced risk of MI (OR = 0.70); the presence of the subunit B arg95 allele had little association with MI risk. However, a significant factor XIII subunit gene-gene interaction was found. Compared to women homozygous for both common factor XIII alleles (val34 and his95), the arg95 variant was associated with a reduced risk of MI in the presence of the leu34 variant (OR = 0.36), but not in its absence (OR = 1.11). Among women who had at least 2 copies of the variant factor XIII alleles and were current estrogen users, the risk of MI was reduced by 70% relative to estrogen nonusers with fewer than 2 factor XIII variant alleles.
In 2 Italian sisters with factor XIII deficiency (613235) and no F13B antigen detected in plasma, Izumi et al. (1996) identified a homozygous 3-bp insertion (AAC) in exon 3 of the F13B gene, resulting in the creation of a premature stop codon and a truncated protein composed of 79 amino acids.
In a Japanese patient with F13B deficiency (613235) who showed postoperative bleeding, Koseki et al. (2001) identified compound heterozygosity for 2 mutations in the F13B gene: a 1-bp deletion (g.14522delG) in exon 9 resulting in a frameshift and premature termination, and the 1-bp deletion in intron A (134580.0001). In vitro functional expression studies of the 1-bp deletion showed impaired secretion and retention of the truncated protein in the endoplasmic reticulum.
Bender, K., Bissbort, S., Klein, A., Mauff, G., Mayerova, A., Nagel, M., Schilling, A., Wienker, T. F. Coagulation factor XIII: genetic linkage studies with F13B. Genet. Epidemiol. 4: 43-49, 1987. [PubMed: 3471677] [Full Text: https://doi.org/10.1002/gepi.1370040106]
Board, P. G. Genetic polymorphism of the B subunit of human coagulation factor XIII. Am. J. Hum. Genet. 32: 348-353, 1980. [PubMed: 7386462]
Board, P. G. Genetic heterogeneity of the B subunit of coagulation factor XIII: resolution of type 2. Ann. Hum. Genet. 48: 223-228, 1984. [PubMed: 6380396] [Full Text: https://doi.org/10.1111/j.1469-1809.1984.tb01018.x]
Eiberg, H., Mohr, J., Nielsen, L. S. Linkage relationships of human coagulation factor XIIIB. (Abstract) Cytogenet. Cell Genet. 37: 463 only, 1984.
Eiberg, H., Neilsen, L. S., Mohr, J. Human complement factor H (HF) linked to coagulation factor XIIIB. (Abstract) Cytogenet. Cell Genet. 46: 610 only, 1987.
Eiberg, H., Schmiegelow, K., Koch, C., Mohr, J., Schwartz, M., Niebuhr, E. Cystic fibrosis; hint of linkage with F13B. Clin. Genet. 27: 206 only, 1985. [PubMed: 3856494] [Full Text: https://doi.org/10.1111/j.1399-0004.1985.tb00213.x]
Grundmann, U., Nerlich, C., Rein, T., Zettlmeissl, G. Complete cDNA sequence encoding the B subunit of human factor XIII. Nucleic Acids Res. 18: 2817-2818, 1990. [PubMed: 2339067] [Full Text: https://doi.org/10.1093/nar/18.9.2817]
Hashiguchi, T., Saito, M., Morishita, E., Matsuda, T., Ichinose, A. Two genetic defects in a patient with complete deficiency of the beta-subunit for coagulation factor XIII. Blood 82: 145-150, 1993. [PubMed: 8324218]
Hing, S., Day, A. J., Linton, S. J., Ripoche, J., Sim, R. B., Reid, K. B. M., Solomon, E. Assignment of complement components C4 binding protein (C4BP) and factor H (FH) to human chromosome 1q, using cDNA probes. Ann. Hum. Genet. 52: 117-122, 1988. [PubMed: 2977721] [Full Text: https://doi.org/10.1111/j.1469-1809.1988.tb01086.x]
Ichinose, A., McMullen, B.A., Fujikawa, K., Davie, E. W. Amino acid sequence of the b subunit of human factor XIII, a protein composed of ten repetitive segments. Biochemistry 25: 4633-4638, 1986. [PubMed: 3021194] [Full Text: https://doi.org/10.1021/bi00364a027]
Izumi, T., Hashiguchi, T., Castaman, G., Tosetto, A., Rodeghiero, F., Girolami, A., Ichinose, A. 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 87: 2769-2774, 1996. [PubMed: 8639893]
Kamboh, M. I., Ferrell, R. E. Genetic studies of low abundance human plasma proteins. II. Population genetics of coagulation factor XIIIB. Am. J. Hum. Genet. 39: 817-825, 1986. [PubMed: 3467588]
Kera, Y., Nishimukai, H., Yamasawa, K. Genetic polymorphism of the B subunit of human coagulation factor XIII: another classification. Hum. Genet. 59: 360-364, 1981. [PubMed: 6949857] [Full Text: https://doi.org/10.1007/BF00295472]
Komanasin, N., Catto, A. J., Futers, T. S., Van Hylckama Vleig, A., Rosendaal, F. R., Ariens, R. A. S. A novel polymorphism in the factor XIII B-subunit (His95Arg): relationship to subunit dissociation and venous thrombosis. J. Thromb. Haemost. 3: 2487-2496, 2005. [PubMed: 16241947] [Full Text: https://doi.org/10.1111/j.1538-7836.2005.01624.x]
Koseki, S., Souri, M., Koga, S., Yamakawa, M., Shichishima, T., Maruyama, Y., Yanai, F., Ichinose, A. Truncated mutant B subunit for factor XIII causes its deficiency due to impaired intracellular transportation. Blood 97: 2667-2672, 2001. Note: Erratum: Blood 97: 3712 only, 2001. [PubMed: 11313256] [Full Text: https://doi.org/10.1182/blood.v97.9.2667]
Leppert, M., Ferrell, R., Kamboh, M. I., Beasley, J., O'Connell, P., Lathrop, M., Lalouel, J.-M., White, R. Linkage of the polymorphic protein markers F13B, C1S, C1R, and blood group antigen Kidd in CEPH reference families. (Abstract) Cytogenet. Cell Genet. 46: 647 only, 1987.
Nakamura, S., Abe, K. Genetic polymorphism of coagulation factor XIIIB subunit in Japanese. Ann. Hum. Genet. 46: 203-207, 1982. [PubMed: 7125593] [Full Text: https://doi.org/10.1111/j.1469-1809.1982.tb00712.x]
Nishigaki, T., Omoto, K. Genetic polymorphism of the B subunit of human coagulation factor XIII in Japanese. Jpn. J. Hum. Genet. 27: 265-270, 1982.
Nonaka, M., Matsuda, Y., Shiroishi, T., Moriwaki, K., Nonaka, M., Natsuume-Sakai, S. Molecular cloning of the b subunit of mouse coagulation factor XIII and assignment of the gene to chromosome 1: close evolutionary relationship to complement factor H. Genomics 15: 535-542, 1993. [PubMed: 8468048] [Full Text: https://doi.org/10.1006/geno.1993.1106]
Reiner, A. P., Heckbert, S. R., Vos, H. L., Ariens, R. A. S., Lemaitre, R. N., Smith, N. L., Lumley, T., Rea, T. D., Hindorff, L. A., Schellenbaum, G. D., Rosendaal, F. R., Siscovick, D. S., Psaty, B. M. Genetic variants of coagulation factor XIII, postmenopausal estrogen therapy, and risk of nonfatal myocardial infarction. Blood 102: 25-30, 2003. [PubMed: 12456499] [Full Text: https://doi.org/10.1182/blood-2002-07-2308]
Rodriguez de Cordoba, S., Rey-Campos, J., Dykes, D. D., McAlpine, P. J., Wong, P., Rubinstein, P. Coagulation factor XIII B subunit is encoded by a gene linked to the regulator of complement activation (RCA) gene cluster in man. Immunogenetics 28: 452-454, 1988. [PubMed: 3182017] [Full Text: https://doi.org/10.1007/BF00355378]
Roychoudhury, A. K., Nei, M. Human Polymorphic Genes: World Distribution. New York: Oxford Univ. Press (pub.) 1988.
Saito, M., Asakura, H., Yoshida, T., Ito, K., Okafuji, K., Yoshida, T., Matsuda, T. A familial factor XIII subunit B deficiency. Brit. J. Haemat. 74: 290-294, 1990. [PubMed: 2334637] [Full Text: https://doi.org/10.1111/j.1365-2141.1990.tb02585.x]
Takahashi, N., Takahashi, Y., Putnam, F. W. Primary structure of blood coagulation factor XIIIa (fibrinoligase, transglutaminase) from human placenta. Proc. Nat. Acad. Sci. 83: 8019-8023, 1986. [PubMed: 2877456] [Full Text: https://doi.org/10.1073/pnas.83.21.8019]
Webb, G. C., Coggan, M., Ichinose, A., Board, P. G. Localization of the coagulation factor XIIIB subunit gene (F13B) to chromosome bands 1q31-32.1 and restriction fragment length polymorphism at the locus. Hum. Genet. 81: 157-160, 1989. [PubMed: 2563250] [Full Text: https://doi.org/10.1007/BF00293893]