Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: B4GALT1
SNOMEDCT: 725587007;
Cytogenetic location: 9p21.1 Genomic coordinates (GRCh38) : 9:33,104,077-33,185,089 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9p21.1 | Combined low LDL and fibrinogen | 620364 | Autosomal recessive | 3 |
| Congenital disorder of glycosylation, type IId | 607091 | Autosomal recessive | 3 |
The enzyme galactosyltransferase (EC 2.4.1.38) catalyzes the reaction involving UDP-galactose and N-acetylglucosamine for the production of galactose beta-1,4-N-acetylglucosamine. The galactosyltransferase enzyme can also form a heterodimer with the regulatory protein alpha-lactalbumin to form lactose synthetase (EC 2.4.1.22). In addition to a biosynthetic role, galactosyltransferases may be components of plasma membranes where they may function in intercellular recognition and/or adhesion. Masri et al. (1988) noted that galactosyltransferase, which they called beta-1,4-galactosyltransferase, is located primarily in the trans-cisternae of the Golgi complex and exists in both membrane-bound and soluble forms.
Appert et al. (1986) cloned a galactosyltransferase cDNA by screening a human liver cDNA library with a probe based on the sequence of the purified protein. The partial cDNA did not include the putative N-terminal membrane-bound region. By screening a human placenta cDNA library with the partial galactosyltransferase cDNA isolated by Appert et al. (1986), Masri et al. (1988) cloned a full-length beta-1,4-galactosyltransferase cDNA. It encodes a predicted 400-amino acid protein with an N-terminal membrane-anchoring domain. The soluble form of the enzyme appears to result from proteolytic cleavage of the membrane-bound form at arginine-77.
By Northern blot analysis, Mengle-Gaw et al. (1991) determined that B4GALT1 was expressed as a 4.2-kb mRNA in all cell lines examined; there was a high degree of variability in expression levels among the cell lines.
By immunolocalization in human umbilical vein endothelial cells, Schnyder-Candrian et al. (2000) localized B4GALT1 with fucosyltransferase-6 (FUT6; 136836) in compact juxtanuclear structures typical of the Golgi apparatus. They noted incomplete overlap of staining.
Mengle-Gaw et al. (1991) reported that the galactosyltransferase gene, which they called GalTase, contains 6 exons spanning more than 50 kb.
Appert et al. (1986) mapped the galactosyltransferase gene to chromosome 9. Shaper et al. (1986) localized the structural gene for galactosyltransferase to 9p13 by in situ hybridization using a cloned bovine cDNA probe. On the basis of dosage effects, Furukawa et al. (1986) suggested that several galactosyltransferase genes may be located on chromosome 17 of the mouse; trisomy 17 embryos had enzyme activities almost 1.5 times higher than did diploid embryos. Furukawa et al. (1986) suggested a relationship between these galactosyltransferases and the major histocompatibility complex.
Lee et al. (2009) stated that B3GNT1 (605517) and B4GALT1 alternately polymerize N-acetylglucosamine and galactose residues, respectively, for the formation of poly-N-acetyllactosamine, a linear carbohydrate that can be incorporated into either N- or O-linked glycans. Using transfected HeLa and COS-1 cells for immunofluorescence and coimmunoprecipitation analysis, respectively, they found that B3GNT1 and B4GALT1 interact directly and colocalize to the Golgi. Addition of an endoplasmic reticulum (ER) retention signal to the C terminus of either enzyme caused relocalization of both to the ER.
Congenital Disorder of Glycosylation Type IId
In a patient with congenital disorder of glycosylation type IId (CDG2D; 607091), a severe neurologic disease characterized by a hydrocephalus, myopathy, and blood clotting defects, Hansske et al. (2002) found deficiency of B4GALT1. Analysis of oligosaccharides from serum transferrin revealed loss of sialic acid and galactose residues. In skin fibroblasts and leukocytes, galactosyltransferase activity was reduced to 5% that of controls, and a truncated polypeptide was detected in fibroblasts that was about 12 kD smaller than wildtype B4GALT1. The protein also failed to localize to the Golgi apparatus. Sequencing of the cDNA revealed a single nucleotide insertion (1031insC; 137060.0001), leading to a premature translation stop and loss of the C-terminal 50 amino acids. Expression of the mutant cDNA in COS-7 cells led to the synthesis of a truncated, inactive polypeptide which localized to the endoplasmic reticulum.
Staretz-Chacham et al. (2020) identified a homozygous missense mutation in the B4GALT1 gene (R21W; 137060.0003) in 3 members of a consanguineous Bedouin Israeli family with CDG2D. The mutation, which was identified by homozygosity mapping and whole-exome sequencing, segregated with the disorder in the family. Glycosylation analysis in serum of 2 affected individuals showed a moderate elevation of Man3GlcNAc4Fuc1.
Combined Low LDL and Fibrinogen
Montasser et al. (2021) identified an association between an Amish-enriched asn352-to-ser (N352S; 137060.0004) variant in a functional domain of the B4GALT1 gene with lower LDL cholesterol (13.9 mg/dl lower; p = 4.1 x 10-19) and lower plasma fibrinogen (29 mg/d lower mg/dl; p = 1.3 x 10-5) (CLDLFIB; 620364). The mean level of AST in N352S homozygotes was 2-fold higher than that in 352N homozygotes (35.8 vs 18.4 U/L, normal range 10-35 U/L, p = 5.9 x 10-17). Whereas 352N homozygotes had normal tri-sialo/di-oligosaccharide transferrin rations, this ratio in 352S homozygotes was abnormal (p = 9.2 x 10-10). B4GALT1 gene-based analysis in 544,955 individuals showed an association of 352S with decreased risk of coronary artery disease (OR = 0.64, p = 0.006).
To identify genetic variants in LDL-C, Montasser et al. (2021) performed whole-exome sequencing and association analysis in 6,890 Old Order Amish. Linear mixed-model association analysis identified previously ascertained loci for LDL-C as well as a novel locus on the short arm of chromosome 9. The N352S missense variant was identified in the B4GALT1 gene. The variant was located in the flexible long C-terminal region of the protein that undergoes conformational changes to allow for the exchange of the sugar molecule during glycosylation. Montasser et al. (2021) suggested that a mutation in this region may impede the necessary conformational change and effect glycosylation efficiency in the regulation of lipid metabolism and fibrinogen levels. The N352S variant had a minor allele frequency of 6% in the Old Order Amish but only 8 copies were identified in 140,000 whole-genome sequences of non-Amish individuals in the NHLBI TOPMed program.
Lo et al. (1998) analyzed 6 members of the B4GALT galactosyltransferase family. Northern blot analysis revealed that, among these homologs, only B4GALT1 is expressed in the mouse lactating mammary gland. They stated that B4galt1-null mice are unable to produce lactose. Thus, B4GALT1 appears to be the gene recruited for lactose biosynthesis during the evolution of mammals.
Asano et al. (1997) produced GalT-knockout mice by gene targeting. GalT-deficient mice were born normally and were fertile, but exhibited growth retardation and semilethality. Epithelial cell proliferation of the skin and small intestine was enhanced, and cell differentiation in intestinal villi was abnormal. The authors concluded that GalT is dispensable during embryonic development, but important in the regulation of proliferation and differentiation of epithelial cells after birth.
Kotani et al. (2001) studied the glycoproteins synthesized by B4GALT1 knockout mice. They observed a shift in the galactose linkages from the largely beta-1,4 linkage with GlcNAc in wildtype mice, to beta-1,3 linkage in knockout mice. This change resulted in the shift of the backbone structure from a type 2 chain to a type 1 chain. Analysis of N-glycans of plasma glycoproteins revealed a shift in sialyl linkages and oversialylated type 1 chains. These results suggested that B4GALT1 deficiency was compensated for by beta-1,3-galactosyltransferases (see B3GALT1, 603093), resulting in altered backbone structures or altered sialyl linkages on outer chains, depending on the acceptor specificities of sialyltransferases.
Humphreys-Beher et al. (1986) isolated a cDNA clone for what they believed to be human 4-beta-galactosyltransferase from a human liver expression library and mapped the gene (GGTB1) to chromosome 4 by Southern analysis of a somatic cell hybrid panel. In an erratum, the authors reported that the antibody used for the isolation of the cDNA clone was not monospecific. Analysis of the complete nucleotide sequence and expression of the cDNA clone showed that it was not the catalytic enzyme.
In a patient with congenital disorder of glycosylation type IId (CDG2D; 607091), Hansske et al. (2002) identified a single nucleotide insertion at position 1031 (1031insC) of the B4GALT1 gene, resulting in a premature translation stop and loss of 50 amino acids at the C terminus. The resultant inactive protein was retained in the endoplasmic reticulum. The patient was homozygous and his parents heterozygous for the mutation.
In a 4-year-old girl with congenital disorder of glycosylation type IId (CDG2D; 607091), Medrano et al. (2019) identified a homozygous c.579C-G transversion (c.579C-G, NM_001497) in the B4GALT1 gene, resulting in a tyr193-to-ter (Y193X) substitution. Segregation analysis showed that the patient's mother carried the mutation but her father did not. Family microsatellite marker segregation analysis confirmed the presence of maternal isodisomy of chromosome 9, leading to homozygosity of the mutation.
In 3 members of a consanguineous Bedouin Israeli family with congenital disorder of glycosylation type IId (CDG2D; 607091), Staretz-Chacham et al. (2020) identified a homozygous c.61C-T transition (c.61C-T, NM_001497.3) in the B4GALT1 gene, resulting in an arg21-to-trp (R21W) substitution in the transmembrane domain. The mutation, which was identified by homozygosity mapping and whole-exome sequencing, segregated with the disorder in the family. The variant was present in the gnomAD database in 3 of 253,694 alleles with no homozygotes reported, and it was not found in 236 ethnically matched controls. The mutation was predicted to affect both the protein structure and function. (In the article by Staretz-Chacham et al. (2020), the mutation is designated R21W in figure 1 (E, F, G) but as R185W in the figure legend. Staretz-Chacham (2021) confirmed that R21W is correct.)
Montasser et al. (2021) identified an association between an Amish-enriched asn352-to-ser (N352S) mutation in a functional domain of the B4GALT1 gene with low LDL cholesterol and plasma fibrinogen (CLDLFIB; 620364). The variant is located in the flexible long C-terminal region of the protein that undergoes conformational changes to allow for the exchange of the sugar molecule during glycosylation. Montasser et al. (2021) suggested that a mutation in this region may impede the necessary conformational change and effect glycosylation efficiency in the regulation of lipid metabolism and fibrinogen levels. The mean level of aspartate aminotransferase (AST) in N352S homozygotes was 2-fold higher than that in 352N homozygotes (35.8 vs 18.4 U/L, normal range 10-35 U/L, p = 5.9 x 10-17).
Appert, H. E., Rutherford, T. J., Tarr, G. E., Wiest, J. S., Thomford, N. R., McCorquodale, D. J. Isolation of a cDNA coding for human galactosyltransferase. Biochem. Biophys. Res. Commun. 139: 163-168, 1986. [PubMed: 3094506] [Full Text: https://doi.org/10.1016/s0006-291x(86)80094-8]
Appert, H., Rutherford, T., Tarr, G., Wiest, J., Thomford, N., McCorquodale, M., McCorquodale, D. J. Isolation of a cDNA for human galactosyltransferase. (Abstract) Am. J. Hum. Genet. 39: A186 only, 1986.
Asano, M., Furukawa, K., Kido, M., Matsumoto, S., Umesaki, Y., Kochibe, N., Iwakura, Y. Growth retardation and early death of beta-1,4-galactosyltransferase knockout mice with augmented proliferation and abnormal differentiation of epithelial cells. EMBO J. 16: 1850-1857, 1997. [PubMed: 9155011] [Full Text: https://doi.org/10.1093/emboj/16.8.1850]
Duncan, A. M. V., McCorquodale, M. M., Morgan, C., Rutherford, T. J., Appert, H. E., McCorquodale, D. J. Chromosomal localization of the gene for a human galactosyltransferase (GT-1). Biochem. Biophys. Res. Commun. 141: 1185-1188, 1986. [PubMed: 3101678] [Full Text: https://doi.org/10.1016/s0006-291x(86)80169-3]
Furukawa, K., Roth, S., Sawicki, J. Several galactosyltransferase activities are associated with mouse chromosome 17. Genetics 114: 983-991, 1986. [PubMed: 3098628] [Full Text: https://doi.org/10.1093/genetics/114.3.983]
Hansske, B., Thiel, C., Lubke, T., Hasilik, M., Honing, S., Peters, V., Heidemann, P. H., Hoffmann, G. F., Berger, E. G., von Figura, K., Korner, C. Deficiency of UDP-galactose:N-acetylglucosamine beta-1,4-galactosyltransferase I causes the congenital disorder of glycosylation type IId. J. Clin. Invest. 109: 725-733, 2002. [PubMed: 11901181] [Full Text: https://doi.org/10.1172/JCI14010]
Humphreys-Beher, M. G., Bunnell, B., vanTuinen, P., Ledbetter, D. H., Kidd, V. J. Molecular cloning and chromosomal localization of human 4-beta-galactosyltransferase. Proc. Nat. Acad. Sci. 83: 8918-8922, 1986. Note: Erratum: Proc. Nat. Acad. Sci. 86: 8747 only, 1989. [PubMed: 3097639] [Full Text: https://doi.org/10.1073/pnas.83.23.8918]
Kotani, N., Asano, M., Iwakura, Y., Takasaki, S. Knockout of mouse beta-1,4-galactosyltransferase-1 gene results in a dramatic shift of outer chain moieties of N-glycans from type 2 to type 1 chains in hepatic membrane and plasma glycoproteins. Biochem. J. 357: 827-834, 2001. [PubMed: 11463354] [Full Text: https://doi.org/10.1042/0264-6021:3570827]
Lee, P. L., Kohler, J. J., Pfeffer, S. R. Association of beta-1,3-N-acetylglucosaminyltransferase 1 and beta-1,4-galactosyltransferase 1, trans-Golgi enzymes involved in coupled poly-N-acetyllactosamine synthesis. Glycobiology 19: 655-664, 2009. [PubMed: 19261593] [Full Text: https://doi.org/10.1093/glycob/cwp035]
Lo, N.-W., Shaper, J. H., Pevsner, J., Shaper, N. L. The expanding beta-4-galactosyltransferase gene family: messages from the databanks. Glycobiology 8: 517-526, 1998. [PubMed: 9597550] [Full Text: https://doi.org/10.1093/glycob/8.5.517]
Masri, K. A., Appert, H. E., Fukuda, M. N. Identification of the full-length coding sequence for human galactosyltransferase (beta-N-acetylglucosaminide: beta-1,4-galactosyltransferase). Biochem. Biophys. Res. Commun. 157: 657-663, 1988. [PubMed: 3144273] [Full Text: https://doi.org/10.1016/s0006-291x(88)80300-0]
Medrano, C., Vega, A., Navarrete, R., Ecay, M. J., Calvo, R., Pascual, S. I., Ruiz-Pons, M., Toledo, L., Garcia-Jimenez, I., Arroyo, I., Campo, A., Couce, M. L., and 18 others. Clinical and molecular diagnosis of non-phosphomannomutase 2 N-linked congenital disorders of glycosylation in Spain. Clin. Genet. 95: 615-626, 2019. [PubMed: 30653653] [Full Text: https://doi.org/10.1111/cge.13508]
Mengle-Gaw, L., McCoy-Haman, M. F., Tiemeier, D. C. Genomic structure and expression of human beta-1,4-galactosyltransferase. Biochem. Biophys. Res. Commun. 176: 1269-1276, 1991. [PubMed: 1903938] [Full Text: https://doi.org/10.1016/0006-291x(91)90423-5]
Montasser, M. E., Van Hout, C. V., Miloscio, L., Howard, A. D., Rosenberg, A., Callaway, M., Shen, B., Li, N., Locke, A. E., Verweij, N., De, T., Ferreira, M. A., and 27 others. Genetic and functional evidence links a missense variant in B4GALT1 to lower LDL and fibrinogen. Science 374: 1221-1227, 2021. [PubMed: 34855475] [Full Text: https://doi.org/10.1126/science.abe0348]
Schnyder-Candrian, S., Borsig, L., Moser, R., Berger, E. G. Localization of alpha-1,3-fucosyltransferase VI in Weibel-Palade bodies of human endothelial cells. Proc. Nat. Acad. Sci. 97: 8369-8374, 2000. [PubMed: 10900002] [Full Text: https://doi.org/10.1073/pnas.97.15.8369]
Shaper, N. L., Shaper, J. H., Bertness, V., Chang, H., Kirsch, I. R., Hollis, G. F. The human galactosyltransferase gene is on chromosome 9 at band p13. Somat. Cell Molec. Genet. 12: 633-636, 1986. [PubMed: 3097837] [Full Text: https://doi.org/10.1007/BF01671948]
Shaper, N. L., Shaper, J. H., Meuth, J. L., Fox, J. L., Chang, H., Kirsch, I. R., Hollis, G. F. Bovine galactosyltransferase: identification of a clone by direct immunological screening of a cDNA expression library. Proc. Nat. Acad. Sci. 83: 1573-1577, 1986. [PubMed: 2419911] [Full Text: https://doi.org/10.1073/pnas.83.6.1573]
Staretz-Chacham, O., Noyman, I., Wormser, O., Quider, A. A., Hazan, G., Morag, I., Hadar, N., Raymond, K., Birk, O. S., Ferreira, C. R., Koifman, A. B4GALT1-congenital disorders of glycosylation: expansion of the phenotypic and molecular spectrum and review of the literature. Clin. Genet. 97: 920-926, 2020. [PubMed: 32157688] [Full Text: https://doi.org/10.1111/cge.13735]
Staretz-Chacham, O. Personal Communication. Beer Sheva, Israel 2/20/2021.