Alternative titles; symbols
HGNC Approved Gene Symbol: TCN2
SNOMEDCT: 237934001; ICD10CM: D51.2;
Cytogenetic location: 22q12.2 Genomic coordinates (GRCh38): 22:30,607,174-30,627,271 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 22q12.2 | Transcobalamin II deficiency | 275350 | Autosomal recessive | 3 |
The TCN2 gene encodes transcobalamin II (TC II), a plasma globulin that acts as the primary transport protein for vitamin B12 (Hakami et al., 1971).
The human TCN2 gene, also referred to as TC2, was cloned by Platica et al. (1991) and Li et al. (1993). Regec et al. (1995) cloned the TCN2 gene and showed that it contains a polyadenylation signal sequence located 509 bp downstream from the termination codon and a transcription initiation site beginning 158 bp upstream from the ATG translation start site. The 5-prime flanking DNA does not have a TATA or CCAAT regulatory element, but a 34-nucleotide stretch beginning just upstream of the CAP site contains 4 tandemly organized 5-prime-CCCC-3-prime tetramers. This sequence is a motif for a trans-active transcription factor (ETF) that regulates expression of the epidermal growth factor receptor gene (EGFR; 131550), which also lacks TATA and CCAAT regulatory elements (Kageyama et al., 1989).
Li et al. (1995) isolated the TCN2 gene and showed that it contains 9 exons and spans about 20 kb. The organization of the gene with respect to the number, size, and position of the exons is similar to that of the other cobalamin-binding proteins human gastric intrinsic factor (GIF, TCN3) and TCN1 (189905). Analysis of the promoter indicated that, unlike GIF and TCN1, TCN2 is a housekeeping gene.
Regec et al. (1995) stated that a number of the exon/intron splice junctions of human TCN2, TCN1, and TCN3 genes are located in homologous regions, providing evidence that they evolved by duplication of an ancestral gene.
Eiberg et al. (1986) showed that TCN2 and blood group P (111400) are linked on chromosome 22; the maximum lod score was 7.91 at theta = 0.14 for males and theta = 0.20 for females.
Arwert et al. (1986) mapped the TCN2 gene to chromosome 22 by somatic cell hybridization. They also showed that meningioma cells obtained from patients heterozygous for TCN2 showed a concomitant loss of one chromosome 22 and one of the two TCN2 alleles, which strongly supported the assignment to chromosome 22.
Li et al. (1995) mapped the genomic clone for TC2 to chromosome 22q12-q13 by fluorescence in situ hybridization.
In mice, Frater-Schroder et al. (1985) used somatic cell hybrids, recombinant inbred (RI) mouse strains, and backcross breeding experiments to map the Tcn2 locus to chromosome 11, linked to the alpha-globin (see 141800) locus (recombination frequency = 19.2%).
Barshop et al. (1990) presented evidence that TC II as well as intrinsic factor (609342) is required for transport of cobalamin from the intestine to the blood. TC II is immunologically, biochemically, and functionally distinct from the R binder protein (189905).
Arwert et al. (1986) demonstrated that TC II is synthesized by cells in culture and secreted into the medium.
Transcobalamin II Polymorphisms
In a study of about 100 Caucasians and in subsequent family studies, Daiger et al. (1975) found evidence for 4 alleles of transcobalamin. However, they could not distinguish TC I and TC II. Frater-Schroder and Hitzig (1977) showed that TC II is the site of the variation.
Genetic heterogeneity of the TC II protein was demonstrated by Frater-Schroder et al. (1979), who applied their analytic methods to the improved detection of carriers (of silent alleles, for example). At least 5 alleles were identified.
Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988).
A pro259-to-arg (P259R) mutation (613441.0002) is the most common polymorphism of the TCN2 gene in white populations. Miller et al. (2002), among others, examined the influence of TCN2 genotype on indices of B12 status; specifically, they studied total serum B12, the amount of B12 bound to TC II, methylmalonic acid, and homocysteine in 128 healthy older adults (ages 40 to 88 years). Mean total B12 and homocysteine concentrations were not significantly different among the 3 genotypes. Mean concentration of bound B12 was significantly higher in those subjects homozygous for the proline form of TC II compared with those homozygous for the arginine form and heterozygotes (p = 0.006). In addition, mean methylmalonic acid concentrations were significantly lower in the proline homozygous and heterozygous groups compared with the arginine homozygous group (p less than or equal to 0.02). The proline homozygous genotype may be more efficient in delivering B12 to tissues, resulting in enhanced B12 functional status. TCN2 genotype may thus influence susceptibility to B12 deficiency.
Afman et al. (2002) studied 5 SNPs in the coding region of the TC2 gene in 42 mothers of neural tube defect (NTD) children and 73 healthy female controls. None of the genotypes defined by the SNPs was associated significantly with elevated plasma homocysteine concentration or with a significantly increased risk for NTD. Three of the SNPs affected total-TC concentration, whereas an effect on holo-TC concentration (proportion of TC that contains vitamin B12) was observed only for the P259R polymorphism (613441.0002), which may be explained by a disturbed binding of vitamin B12 to TC due to a change in the secondary structure of the TC protein.
Transcobalamin II Deficiency
Since TC2 synthesis had been demonstrated in cultured skin fibroblasts from normal patients, Li et al. (1994) studied skin fibroblasts from a child with transcobalamin II deficiency (TCN2D; 275350) and his parents. They found that the affected child was a compound heterozygote with a gross deletion of the maternally derived allele and a 4-bp deletion in the coding region of the paternally derived allele (613441.0001). Both of these deletions caused markedly reduced levels of TC2 mRNA and protein.
In 3 patients, including 2 sibs, with TC II deficiency, Haberle et al. (2009) identified 2 different homozygous mutations in the TCN2 gene (613441.0004 and 613441.0005, respectively).
Cavalli-Sforza et al. (1979) found a suggestion of linkage of the TCN2 locus and adenylate kinase (AK1; 103000); lod score = 1.78 at theta = 0.139. Linkage studies by Ott and Frater-Schroder (1981) excluded TCN2 versus ABO linkage, however. Yang et al. (1981) could find no evidence of linkage with several loci, including ABO, AK1, ADA, GLO1, PI, and HLA.
Arwert et al. (1983) reported that transcobalamin II (symbolized Tcn2 in the mouse) is linked to the alpha-globin locus and the esterase-3 (Es3) locus on mouse chromosome 11. In the mouse, classic linkage studies could not confirm linkage to Es3. The recombination frequency between Hba and Tcn2 was 10.2% in one series of experiments and in other experiments with 5 different inbred strains the mean was 14% (range, 7% to 24%) (Acklin et al., 1984).
In a patient with transcobalamin II deficiency (TCN2D; 275350), Li et al. (1994) found compound heterozygosity for a gross deletion of the TCN2 maternal allele and a 4-bp deletion at nucleotide 1022 (codon 309) on the paternal allele, leading to a premature termination codon at nucleotide 1172 (codon 359).
Haberle et al. (2009) referred to this mutation as 926_931del4, resulting in a frameshift and premature termination (fs358X).
Miller et al. (2002) stated that the most common polymorphism in the TC II gene among white populations is a G-to-C transversion at base position 775, resulting in a pro259-to-arg (P259R) mutation.
Zetterberg et al. (2003) noted that this polymorphism is a C-to-G substitution at position 776 in relation to the first nucleotide (+1) of the ATG translation initiation codon, not a G-to-C transversion at position 775 as reported by Miller et al. (2002).
Gueant et al. (2007) studied the worldwide distribution of the TCN2 776G allele in 1,433 apparently healthy individuals from Europe, the Mediterranean, West Africa, China, Mexico, and the U.S., and in 251 West Africans with severe malaria. There was heterogeneity in allele distribution worldwide, with the highest 776G allele frequency in China, where it was even more frequent than the 776C allele. By comparison, the 776G allele was 3.4-fold and 1.5-fold lower in West African and Caucasian populations, respectively. There was a 2-fold increased frequency of the 776G genotype in West African patients with severe malaria compared to healthy controls from the same geographic area; genotype disequilibrium was also noted, with a 2-fold higher rate of the GG genotype than expected in patients with malaria. Gueant et al. (2007) concluded that the 776G polymorphism may be prone to selective pressure or confer an evolutionary advantage in confronting environmental factors such as malaria.
Bibi et al. (1999) described 3 sisters, born to first-cousin parents, who presented with megaloblastic anemia, thrombocytopenia, and methylmalonic aciduria that responded to vitamin B12 treatment, consistent with TC II deficiency (TCN2D; 275350). In the patients reported by Bibi et al. (1999), Namour et al. (2003) identified a homozygous intron 3 splice site mutation of the TCN2 gene that activated a cryptic splice site in exon 3. The transcript generated had an in-frame deletion of 81 nucleotides and the resulting protein was unstable and not secreted by cells. The authors stated that only 5 patients with TC deficiency had previously been described and the molecular defect was different in each. The 347-348 dinucleotide GT was activated as a surrogate for the mutated donor splice site. Although the protein transcript was shortened, the reading frame was conserved after deletion of 81 nucleotides.
Haberle et al. (2009) referred to this mutation as 427+2T-G (Cys116_Ile142delGly143Trp).
In a Lebanese girl, born of consanguineous parents, with transcobalamin II deficiency (TCN2D; 275350), Haberle et al. (2009) identified a homozygous 2,152-bp deletion spanning introns 6 and 7 and a 4-bp CTGG insertion in the TCN2 gene, resulting in the homozygous deletion of exon 7 and premature termination. The patient had diarrhea, vomiting, hypotonia, and failure to thrive at age 3 weeks. Laboratory studies showed pancytopenia, methylmalonic aciduria, and megaloblastic anemia. Cobalamin supplementation resulted in clinical improvement. The molecular diagnosis was confirmed by examination of skin-derived fibroblast cDNA, since direct sequencing of the TCN2 gene was inconclusive. The unaffected parents were heterozygous for the mutation.
In 2 sibs, born of consanguineous Turkish parents, with transcobalamin II deficiency (TCN2D; 275350), Haberle et al. (2009) identified a homozygous A-to-T transversion in intron 4 of the TCN2 gene, resulting in activation of a cryptic acceptor splice site, insertion of 87 bp, and premature termination. The unaffected parents were heterozygous for the mutation, which was not found in 100 control chromosomes. Both patients had onset in the first weeks of life of failure to thrive, pancytopenia, and methylmalonic aciduria, and both responded to hydroxycobalamin treatment. Both had normal psychomotor development at ages 9 and 11 years, respectively. The molecular diagnosis was confirmed by examination of skin-derived fibroblast cDNA, since direct sequencing of the TCN2 gene was inconclusive.
Acklin, M., Frater-Schroder, M., Haller, O., Lundin, L. G., Prochazka, M., Skow, L. C. Localization of transcobalamin II (Tcn-2) on chromosome 11: linkage to waved-2 (wa-2) and the hemoglobin alpha-chain locus (Hba). Mouse News Lett. 70: 107-108, 1984.
Afman, L. A., Lievers, K. J. A., van der Put, N., Trijbels, F. J. M., Blom, H. J. Single nucleotide polymorphisms in the transcobalamin gene: relationship with transcobalamin concentrations and risk for neural tube defects. Europ. J. Hum. Genet. 10: 433-438, 2002. [PubMed: 12107818] [Full Text: https://doi.org/10.1038/sj.ejhg.5200830]
Arwert, F., Bruderer, S., Frater-Schroder, M., Haller, O., Hilgers, J., Hilkens, J., Porck, H. J., Skow, L. Tentative assignment of transcobalamin II (Tcn-2) to chromosome 11. Mouse News Lett. 69: 56, 1983.
Arwert, F., Geurts van Kessel, A., Porck, H., Frater-Schroder, M., Westerveld, A., Meera Khan, P. Human transcobalamin II (TC2) in man-rodent somatic cell hybrids. (Abstract) Cytogenet. Cell Genet. 37: 404 only, 1984.
Arwert, F., Porck, H. J., Frater-Schroder, M., Brahe, C., Geurts van Kessel, A., Westerveld, A., Meera Khan, P., Zang, K., Frants, R. R., Kortbeek, H. T., Eriksson, A. W. Assignment of human transcobalamin II (TC2) to chromosome 22 using somatic cell hybrids and monosomic meningioma cells. Hum. Genet. 74: 378-381, 1986. [PubMed: 3466852] [Full Text: https://doi.org/10.1007/BF00280489]
Barshop, B. A., Wolff, J., Nyhan, A. L., Yu, A., Prodanos, C., Jones, G., Sweetman, L., Leslie, J., Holm, J., Green, R., Jacobsen, D. W., Cooper, B. A., Rosenblatt, D. Transcobalamin II deficiency presenting with methylmalonic aciduria and homocystinuria and abnormal absorption of cobalamin. Am. J. Med. Genet. 35: 222-228, 1990. [PubMed: 2309761] [Full Text: https://doi.org/10.1002/ajmg.1320350216]
Bibi, H., Gelman-Kohan, Z., Baumgartner, E. R., Rosenblatt, D. S. Transcobalamin II deficiency with methylmalonic aciduria in three sisters. J. Inherit. Metab. Dis. 22: 765-772, 1999. [PubMed: 10518276] [Full Text: https://doi.org/10.1023/a:1005507204491]
Cavalli-Sforza, L. L., King, M. C., Go, R. C. P., Namboodiri, K. K., Lynch, H. T., Wong, L., Kaplan, E. B., Elston, R. C. Possible linkage between transcobalamin II (TC II) and adenylate kinase (AK). (Abstract) Cytogenet. Cell Genet. 25: 140-141, 1979.
Chanarin, I., Muir, M., Hughes, A., Hoffbrand, A. V. Evidence for intestinal origin of transcobalamin II during vitamin B12 absorption. Brit. Med. J. 1: 1453-1455, 1978. [PubMed: 647333] [Full Text: https://doi.org/10.1136/bmj.1.6125.1453]
Daiger, S. P., Labowe, M. L., Cavalli-Sforza, L. L. Polymorphic electrophoretic variants of vitamin B12 binding proteins in human plasma. (Abstract) Am. J. Hum. Genet. 27: 31A only, 1975.
Daiger, S. P., Labowe, M. L., Parsons, M., Wang, L., Cavalli-Sforza, L. L. Detection of genetic variation with radioactive ligands. III. Genetic polymorphism of transcobalamin II in human plasma. Am. J. Hum. Genet. 30: 202-214, 1978. [PubMed: 655167]
Eiberg, H., Moller, N., Mohr, J., Nielsen, L. S. Linkage of transcobalamin II (TC2) to the P blood group system and assignment to chromosome 22. Clin. Genet. 29: 354-359, 1986. [PubMed: 3461892] [Full Text: https://doi.org/10.1111/j.1399-0004.1986.tb00504.x]
Frater-Schroder, M., Hitzig, W. H., Butler, R. Studies on transcobalamin: detection of TC II isoproteins in human serum. Blood 53: 193-203, 1979. [PubMed: 760849]
Frater-Schroder, M., Hitzig, W. H. The transcobalamin II isoprotein pattern. (Abstract) Experientia 33: 791 only, 1977.
Frater-Schroder, M., Porck, H. J., Eriksson, A. W., Daiger, S. P., Cavalli-Sforza, L. L. Standardization of nomenclature for transcobalamin II variants. Hum. Genet. 61: 165-166, 1982. [PubMed: 7129444] [Full Text: https://doi.org/10.1007/BF00274211]
Frater-Schroder, M., Prochazka, M., Haller, O., Arwert, F., Porck, H. J., Skow, L. C., Lundin, L.-G., Hilkens, J., Hilgers, J. Localization of the gene for the vitamin B12 binding protein, transcobalamin II, near the centromere on mouse chromosome 11, linked with the hemoglobin alpha-chain locus. Biochem. Genet. 23: 139-153, 1985. [PubMed: 3857911] [Full Text: https://doi.org/10.1007/BF00499119]
Frater-Schroder, M. Genetic patterns of transcobalamin II and the relationships with congenital defects. Molec. Cell. Biochem. 56: 5-31, 1983. [PubMed: 6355816] [Full Text: https://doi.org/10.1007/BF00228765]
Gallmann, M., Frater-Schroder, M., Scheffrahn, W., Ott, J., Schmid, B., Butler, E., Biedermann, V., Kierat, L. Indication against genetic localisation of the human transcobalamin II gene (TC2) on chromosome 16. Clin. Genet. 29: 349-353, 1986. [PubMed: 3017611] [Full Text: https://doi.org/10.1111/j.1399-0004.1986.tb00503.x]
Gueant, J.-L., Chabi, N. W., Gueant-Rodriguez, R.-M., Mutchinick, O. M., Debard, R., Payet, C., Lu, X., Villaume, C., Bronowicki, J.-P., Quadros, E. V., Sanni, A., Amouzou, E., and 11 others. Environmental influence on the worldwide prevalence of a 776C-G variant in the transcobalamin gene (TCN2). J. Med. Genet. 44: 363-367, 2007. [PubMed: 17220211] [Full Text: https://doi.org/10.1136/jmg.2006.048041]
Haberle, J., Pauli, S., Berning, C., Koch, H. G., Linnebank, M. TC II deficiency: avoidance of false-negative molecular genetics by RNA-based investigations. J. Hum. Genet. 54: 331-334, 2009. [PubMed: 19373259] [Full Text: https://doi.org/10.1038/jhg.2009.34]
Hakami, N., Neiman, P. E., Canellos, G. P., Lazerson, J. Neonatal megaloblastic anemia due to inherited transcobalamin II deficiency in two siblings. New Eng. J. Med. 285: 1163-1170, 1971. [PubMed: 5096637] [Full Text: https://doi.org/10.1056/NEJM197111182852103]
Hitzig, W. H., Kenny, A. B. The role of vitamin B12 and its transport globulins in the production of antibodies. Clin. Exp. Immun. 20: 105-111, 1975. [PubMed: 128427]
Kageyama, R., Merlino, G. T., Pastan, I. Nuclear factor ETF specifically stimulates transcription from promoters without a TATA box. J. Biol. Chem. 264: 15508-15514, 1989. [PubMed: 2768275]
Li, N., Rosenblatt, D. S., Kamen, B. A., Seetharam, S., Seetharam, B. Identification of two mutant alleles of transcobalamin II in an affected family. Hum. Molec. Genet. 3: 1835-1840, 1994. [PubMed: 7849710] [Full Text: https://doi.org/10.1093/hmg/3.10.1835]
Li, N., Seetharam, S., Lindemans, J., Alpers, D. H., Arwert, F., Seetharam, B. Isolation and sequence analysis of variant forms of human transcobalamin II. Biochim. Biophys. Acta 1172: 21-30, 1993. [PubMed: 8439564] [Full Text: https://doi.org/10.1016/0167-4781(93)90264-e]
Li, N., Seetharam, S., Seetharam, B. Genomic structure of human transcobalamin II: comparison to human intrinsic factor and transcobalamin I. Biochem. Biophys. Res. Commun. 208: 756-764, 1995. [PubMed: 7695633] [Full Text: https://doi.org/10.1006/bbrc.1995.1402]
Masina, P., Ramunno, L., Iannelli, D. Evidence for 15 genetically determined electrophoretic variants of transcobalamin II in rabbit serum. Biochem. Genet. 17: 757-767, 1979. [PubMed: 540019] [Full Text: https://doi.org/10.1007/BF00502134]
Miller, J. W., Ramos, M. I., Garrod, M. G., Flynn, M. A., Green, R. Transcobalamin II 775G-to-C polymorphism and indices of vitamin B12 status in healthy older adults. Blood 100: 718-720, 2002. Note: Erratum: Blood 100: 3483 only, 2002. [PubMed: 12091374] [Full Text: https://doi.org/10.1182/blood-2002-01-0209]
Namour, F., Helfer, A.-C., Quadros, E. V., Alberto, J.-M., Bibi, H. M., Orning, L., Rosenblatt, D. S., Jean-Louis, G. Transcobalamin deficiency due to activation of an intra exonic cryptic splice site. Brit. J. Haemat. 123: 915-920, 2003. [PubMed: 14632784] [Full Text: https://doi.org/10.1046/j.1365-2141.2003.04685.x]
Ott, J., Frater-Schroder, M. Absence of linkage between transcobalamin II and ABO. Hum. Genet. 59: 164-165, 1981. [PubMed: 7327575] [Full Text: https://doi.org/10.1007/BF00293068]
Platica, O., Janeczko, R., Quadros, E. V., Regec, A., Romain, R., Rothenberg, S. P. The cDNA sequence and the deduced amino acid sequence of human transcobalamin II show homology with rat intrinsic factor and human transcobalamin I. J. Biol. Chem. 266: 7860-7863, 1991. [PubMed: 1708393]
Porck, H. J., Fleming, A. F., Frants, R. R. Distribution of genetic variants of transcobalamin II in Nigerian black populations. Am. J. Hum. Genet. 36: 710-717, 1984. [PubMed: 6731442]
Porck, H. J., Frater-Schroder, M., Frants, R. R., Kierat, L., Eriksson, A. W. Genetic evidence for fetal origin of transcobalamin II in human cord blood. Blood 62: 234-237, 1983. [PubMed: 6860794]
Quadros, E. V., Rothenberg, S. P., Pan, Y.-C. E., Stein, S. Purification and molecular characterization of human transcobalamin II. J. Biol. Chem. 261: 15455-15460, 1986. [PubMed: 3782074]
Regec, A., Quadros, E. V., Platica, O., Rothenberg, S. P. The cloning and characterization of the human transcobalamin II gene. Blood 85: 2711-2719, 1995. [PubMed: 7742531]
Rosenblatt, D. S., Hosack, A., Matiaszuk, N. Expression of transcobalamin II by amniocytes. Prenatal Diag. 7: 35-39, 1987. [PubMed: 3823005] [Full Text: https://doi.org/10.1002/pd.1970070107]
Roychoudhury, A. K., Nei, M. Human Polymorphic Genes: World Distribution. New York: Oxford Univ. Press (pub.) 1988.
Scott, C. R., Hakami, N., Teng, C. C., Sagerson, R. N. Hereditary transcobalamin II deficiency: the role of transcobalamin II in vitamin B12 dependent reactions in man. J. Pediat. 81: 1106-1111, 1972. [PubMed: 4643028] [Full Text: https://doi.org/10.1016/s0022-3476(72)80239-7]
Yang, S. Y., Coleman, P., Ochs, H. D., Dupont, B. Inheritance and genetic linkage of transcobalamin II. Hum. Genet. 57: 307-311, 1981. [PubMed: 6941922] [Full Text: https://doi.org/10.1007/BF00278950]
Zetterberg, H., Palmer, M., Borestrom, C., Rymo, L., Blennow, K. The transcobalamin codon 259 polymorphism should be designated 776C-G, not 775G-C. (Letter) Blood 101: 3749-3750, 2003. [PubMed: 12707225] [Full Text: https://doi.org/10.1182/blood-2003-01-0084]