Alternative titles; symbols
HGNC Approved Gene Symbol: GC
Cytogenetic location: 4q13.3 Genomic coordinates (GRCh38): 4:71,741,693-71,805,520 (from NCBI)
Human group-specific component (GC) is the major vitamin D-binding protein in plasma (summary by Yang et al., 1985).
By immunoelectrophoresis, Hirschfeld (1959) discovered polymorphism of the serum alpha-2-globulin called Gc for group-specific component. Gc1-1, Gc2-2, and Gc2-1 phenotypes can be distinguished also by starch or agar electrophoresis (Bearn et al., 1964). In the same year that Gc proteins were reported, another human plasma protein, vitamin D-binding alpha-globulin (VDBG), was described (Thomas et al., 1959). Daiger et al. (1975) demonstrated that Gc and VDBG are identical.
Svasti et al. (1979) showed that Gc has a single polypeptide chain with a molecular mass of 52,000 Da. They found that the difference between Gc-1(fast), or GC1f, and Gc-1(slow), or GC1s, is posttranslational, involving carbohydrate differences; the difference between Gc-1 and Gc-2 is related to primary structure.
Yang et al. (1985) cloned human GC cDNA from an adult liver library. The deduced 458-amino acid protein shares 25% and 19% sequence identity with albumin (ALB; 103600) and alpha-fetoprotein (AFP), respectively. The pattern of disulfide bridges that contribute to the double loops forming the 3 domains in each protein is highly conserved.
Yang et al. (1990) found that the deduced amino acid sequence of mouse Gc is 78% identical to human Gc and 91% identical to rat Gc.
Weitkamp et al. (1966) concluded that the albumin locus (ALB; 103600) is closely linked to Gc.
Mikkelsen et al. (1977) presented studies they interpreted as indicating that the Gc locus is on the long arm of chromosome 4. In a mentally retarded girl a segment of that chromosome (4q11-q13) was missing. The patient was Gc2-2, with an abnormally low Gc concentration. Her mother was also Gc2-2 but the father was Gc1-1. No other member of the family showed a decreased Gc level. Previously, the same group (Henningsen et al., 1969) thought that the girl had a reciprocal translocation between the long arm of a group B chromosome and one arm of a group F chromosome. Abnormal segregation of the Gc system was observed in the proposita suggesting either a silent allele in the father or a gene dosage effect (Henningsen et al., 1969). Yamamoto et al. (1989) described a second patient who was possibly hemizygous for the Gc locus and who also had an interstitial deletion of 4q, specifically q12-q21.1. The Gc phenotypes of the propositus, father, and mother were 1F, 1S and 1F, respectively. The serum concentrations of Gc protein in the patient and his father were only about half of those of his mother and control individuals. Thus, it is possible that the father was heterozygous for a silent allele which was transmitted to the son with the de novo deletion.
Linkage of Gc and MNSs at recombination frequencies of less than 25% in males and 30% in females was excluded by Weitkamp (1978). For MN versus Gc, Falk et al. (1979) found a male lod score of 3.75 at a recombination fraction of 0.30, and a female lod score of 0.34 at a recombination fraction of 0.42. Location of MN on chromosome 4q (where Gc has been tentatively placed) is consistent with the findings of German et al. (1969) on a family in which a child with a reciprocal translocation between 2q and 4q was hemizygous at the MN locus. For the linkage of DGI (125490) and GC, Ball et al. (1982) found a maximum lod score of 7.9 at a male recombination fraction of 0.05 and a female recombination fraction of 0.24. The gene order was thought to be 4cen--GC--DGI--MN--4qter. Subtyping of GC was valuable in increasing linkage information in a single large kindred described earlier by Mars et al. (1976).
Schoentgen et al. (1985) and Bowman et al. (1985) presented evidence that GC, ALB, and AFP represent a gene cluster based on evolution from a common ancestral gene. The 3 proteins show strong sequence homology and identical patterns of disulfide bridges that form their triple domain structures. Yang et al. (1985) used GC cDNA as a probe in Southern blot analysis of somatic cell hybrids to confirm assignment of the gene cluster to chromosome 4. Using a cDNA probe, Cooke et al. (1986) assigned the GC locus to chromosome 4 by somatic cell hybridization and regionalized it to 4q11-q13 by in situ hybridization. McCombs et al. (1986) mapped GC to 4q13-q21.1 by in situ hybridization.
Yang et al. (1990) mapped the mouse Gc gene to chromosome 5 where the albumin and alpha-fetoprotein genes are also located.
As reviewed by Shibata and Abe (1996), close genetic linkage between the ALB locus and GC has been reported in humans, horse, cattle, and sheep among mammals and in chicken in avian species. They demonstrated close linkage also in the Japanese quail.
Witke et al. (1993) sequenced the entire GC gene, including 4,228 bp of the 5-prime-flanking region and 8,514 bp of the 3-prime flanking region. The sequence spans 42,394 basepairs from the cap site to the polyadenylation site. The gene is composed of 13 exons. The first exon is partially untranslated, as is exon 12, which contains the termination codon TAG. Exon 13 is entirely untranslated but contains the polyadenylation signal AATAAA. Ten central introns split the coding sequence between codon positions 2 and 3 and between codon positions 3 and 1 in an alternating pattern, exactly as has been observed in the structure of the albumin (ALB; 103600) and alpha-fetoprotein (AFP; 104150) genes. Setting the GC gene apart from the other members, however, are its smaller size by 2 exons, resulting in a protein some 130 amino acids shorter than albumin or AFP, and smaller size of 4 of its exons. Although the mRNA and protein expressed from the GC gene are significantly smaller, the gene itself is about 2.5 times larger than the other genes of the family. This is the consequence of 13 interspersed DNA repeats within the GC gene.
Braun et al. (1993) likewise reported on the sequence and organization of the DBP gene.
The major function of DBP is binding, solubilization, and transport of vitamin D and its metabolites (Daiger et al., 1975).
Yamamoto and Homma (1991) presented evidence from studies in mice that vitamin D-3 binding protein is a precursor for the macrophage-activating factor, that it is converted by the membrane glycosidases of B and T cells to the macrophage-activating factor, and that enzymatic conversion of Gc protein to the macrophage-activating factor can occur in vitro. In vitro treatment of mouse peritoneal adherent cells (macrophages) alone with lysophosphatidylcholine or dodecylglycerol results in no enhanced ingestion activity of macrophages. However, incubation of peritoneal cells with these agents in serum-supplemented medium results in greatly enhanced phagocytic activity. Gc is the serum factor responsible for this. The role of Gc in this function suggests possible mechanisms for maintenance of the Gc polymorphism. Along with gelsolin (137350), the Gc protein binds actin, which is released into the circulation with cell necrosis. This is the so-called extracellular actin-scavenger system which prevents toxic effects of actin.
In a 58-year-old Lebanese woman with severe ankylosing spondylitis (see 106300), who experienced low-trauma fractures and had normocalcemic osteopenia with low to undetectable levels of calcidiol, calcitriol, and secalciferol, Henderson et al. (2019) identified homozygosity for a 139-kb deletion at chromosome 4q13.3 that encompassed the entire GC gene, as well as an adjacent 144-kb deletion involving part of the NPFFR2 gene (607449). Testing of 3 unaffected sibs revealed 2 who were heterozygous for the deletions and 1 who did not carry them; levels of vitamin D metabolites in the noncarrier sib were at or near the normal range, whereas those in the carrier sibs were intermediate.
By immunoelectrophoresis, Hirschfeld (1959) detected 3 common GC phenotypes: GC1-1 (GC1), GC2-1, and GC2-2. See 139200.0001 and 139200.0002, which describe the GC2, CG1F, and CG1S alleles.
Mourant et al. (1976) concluded that high frequency of the Gc(2) allele corresponds, with some exceptions, to low levels of sunlight. Within Ireland, the correlation did not hold.
By a novel method of labeling Gc protein with radioactive vitamin D, followed with electrophoresis and autoradiography, Daiger and Cavalli-Sforza (1977) detected new Gc variants. The gene frequency of some of the variants was as high as 15%. They were testing a physiologically relevant property of the Gc protein.
In Iceland, Karlsson et al. (1980) used immunofixation electrophoresis for Gc typing according to the method of Johnson et al. (1975). They found a new variant first thought to be identical to Gc Norway but later shown to be distinct.
Constans et al. (1983) stated that 84 different mutants had been described; a listing was provided.
Szathmary (1987) found a connection between Gc genotype and the level of fasting insulin in the blood. Their rationale for undertaking the study was that GC binds vitamin D and the metabolically active form of vitamin D is involved in the regulation of insulin levels.
Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988).
Yasuda et al. (1989) described a variant of GC which may have arisen through gene duplication.
Kofler et al. (1995) stated that in addition to the 3 common alleles (GC*2, GC*1S, and GC*1F), more than 120 variant alleles of GC had been identified. The molecular differences of the 3 common alleles reside in exon 11 at codons 416 and 420. At position 416, the codon for aspartic acid (GAT) was found for the alleles GC*1F and GC*2, the codon for glutamic acid (GAG) for GC*1S. At position 420, the codon for threonine (ACG) was found for GC*1F and GC*1S, the codon for lysine (AAG) for GC*2. Position 416 includes a HaeIII restriction site for the allele GC*1S and position 420 includes a StyI restriction site for allele GC*2. Thus, the 3 common genetic GC types can be determined by restriction fragment analysis.
An Australian variant, 1A1, was first reported by Cleve et al. (1963) and called GC Aborigine (GC-Ab). The African variant 1A1 was described by Hirschfeld (1962) and Parker et al. (1963) and was originally called GC-Y. These 2 variants are indistinguishable by all methods for typing based on the physical properties of the protein, raising the possibility that they may represent the same mutation. By studies of genomic DNA carrying the 1A1 variant from Australian Aborigines and from South African Bantu-speaking blacks, Kofler et al. (1995) demonstrated that the 2 are indeed identical. Amplification and sequencing of exon 11 showed in both cases that variant 1A1 has a point mutation in codon 429 at the second position. The finding of the same mutation in 2 widely separated ethnic groups raised the question as to whether the mutation had a common origin. The variant 1A1 mutation occurred in the GC*1F allele.
Baier et al. (1998) analyzed the GC gene as a candidate for linkage to plasma glucose and insulin concentrations in Pima Indians based on their previous findings (Baier and The Pima Diabetes Genes Group, 1996). Sequence analysis of the coding exons identified 2 previously described missense polymorphisms at codons 416 and 420, which are the genetic basis for the 3 common electrophoretic variants of DBP (GC1f, GC1s, and GC2). These DBP variants were associated with differences in oral glucose tolerance in nondiabetic Pima Indians.
The highly polymorphic DBP protein exhibits a geographical distribution of 3 common alleles and a large number of unique racial variants. Populations with a white skin have a relatively lower frequency of the Gc1F allele and a higher frequency (50-60%) of the Gs1S allele. The Gc1F allele frequency is markedly higher among black Americans than among black Africans. The Gc1F and Gc1S allele frequencies display a typical geographical cline from Southeast Asia, through Europe and the Middle East, down to Africa. A common feature of all populations is the lower predominance of the Gc2 allele in comparison with the Gc1 allele. Unlike black populations, Caucasians have a markedly higher Gc2 allele frequency. The observed variation in the Gc allele frequencies in different geographic areas may be correlated with skin pigmentation and intensity of sun light exposure (summary by Speeckaert et al., 2006).
Associations Pending Confirmation
For discussion of a possible association between variation in the GC gene and susceptibility to Graves disease, see 275000.
Eales et al. (1987) conducted a study of immunologic and clinical evidence of human immunodeficiency virus (HIV; see 609423) infection in homosexuals and found that 30.2% of patients with acquired immunodeficiency syndrome (AIDS) were homozygous for the GC1f allele compared with 0.8% of controls. They proposed that Gc may be involved in viral entry into host cells, the ease of which varies with different allelic forms of Gc, according to their sialic acid content. On the other hand, Gilles et al. (1987) and Daiger et al. (1987) concluded that there is no association between Gc genotype and genetic susceptibility to AIDS. Eales et al. (1988) cited erroneous data in their original report and concluded that there is no support for an association between GC1f and HIV disease progression.
No evidence of linkage of Gc, transferrins (190000), ABO, MN, Rh (see 111700), and haptoglobins (140100) was found in a study in Finland (Seppala et al., 1967).
Braun et al. (1992) demonstrated that in the GC2 phenotype amino acid 420 is a lysine residue, whereas it is a threonine residue in both common GC1 phenotypes, GC1F and GC1S. The GC2 and GC1F phenotypes have an aspartic acid residue at amino acid position 416, whereas the GC1S phenotype has a glutamic acid at this position. The nucleotide exchanges involve a HaeIII (position 416) and a StyI (position 420) restriction site; thus, the HaeIII restriction site is specific for the GC*1S allele and the StyI restriction site is specific for the GC*2 allele.
See 139200.0001 and Braun et al. (1992).
Braun et al. (1993) described a polymorphism of the GC gene, a variable (TAAA)n repeat in intron 8 that they referred to as GC-I8. In a population from southern Germany they detected 3 common alleles of this patterned repeat, termed GC-I8*6, GC-I8*8, and GC-I8*10, depending on the number of TAAA unit repeats.
Baier, L. J., Dobberfuhl, A. M., Pratley, R. E., Hanson, R. L., Bogardus, C. Variations in the vitamin D-binding protein (Gc locus) are associated with oral glucose tolerance in nondiabetic Pima Indians. J. Clin. Endocr. Metab. 83: 2993-2996, 1998. [PubMed: 9709981] [Full Text: https://doi.org/10.1210/jcem.83.8.5043]
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