MIM Entry: 139200
+139200 GROUP-SPECIFIC COMPONENT; GC
;;VITAMIN D-BINDING PROTEIN; DBP; VDBP;;
VITAMIN D-BINDING ALPHA-GLOBULIN; VDBG
GRAVES DISEASE, SUSCEPTIBILITY TO, 3, INCLUDED; GRD3, INCLUDED
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. Daiger et al. (1975) demonstrated
that Gc and VDBG are identical. The worldwide polymorphism of Gc is now
not surprising. 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.
Svasti et al. (1979) showed that Gc has a single polypeptide chain of MW
52,000. 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. 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.
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. Eales et al. (1987)
conducted a study of immunologic and clinical evidence of HIV infection
in homosexuals and found that 30.2% of patients with the 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. Yasuda et al. (1989) described a variant of GC which may have
arisen through gene duplication.
Data on gene frequencies of allelic variants were tabulated by
Roychoudhury and Nei (1988).
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
No evidence of linkage of Gc, transferrins (190000), ABO (110300), MN
(111300), Rh (see 111700), and haptoglobins (140100) was found in a
study in Finland (Seppala et al., 1967). See albumin (103600) for
information on linkage with 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 dose 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. The deduced amino acid
sequence of mouse Gc is 78% identical to human and 91% identical to rat
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.
As reviewed by Shibata and Abe (1996), close genetic linkage between the
locus for serum albumin (103600) and GC has been reported in humans,
horse, cattle, and sheep among the mammals and in chicken in avian
species. They demonstrated close linkage also in the Japanese quail.
Braun et al. (1992) reviewed the molecular basis for the polymorphism of
GC, concluding that it was known only in part. They 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).
GRAVES DISEASE, SUSCEPTIBILITY TO, 3, INCLUDED
GC, IVS8, (TAAA)n
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.
The immunomodulatory effects of the vitamin D endocrine system and the
importance of DBP for systemic 1,25-dihydroxyvitamin D led Pani et al.
(2002) to genotype families with an offspring affected by Graves disease
(275000) (95 pedigrees) or by Hashimoto thyroiditis (140300) (92
pedigrees), encompassing 561 individuals of Caucasian origin, for the
T420K (139200.0001), D416E (139200.0002), and intron 8 DBP
polymorphisms. There was a significant transmission disequilibrium of
the intron 8 polymorphism in patients with Graves disease (P less than
0.03) but not of the exon 11 polymorphisms. They found that allele 8 was
significantly more often inherited to patients than was allele 10; the
observed frequency of allele 6 was too low for a statistical evaluation.
In contrast, neither the IVS8 nor the exon 11 polymorphisms were
associated with Hashimoto thyroiditis. Maternal and paternal
transmission as well as allele frequencies in DQ2+ and DQ2- (see 146880)
patients did not differ in either disease. The authors concluded that
allelic variants of the DBP gene confer susceptibility to Graves disease
but not to Hashimoto thyroiditis in their population. They also
concluded that these findings support a role of the vitamin D endocrine
system in thyroid autoimmunity.
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Galbraith (1992); Magenis et al. (1985); Petrini et al. (1983); Pierce
et al. (1985); Rucknagel et al. (1968); Thymann et al. (1982); Vavrusa
et al. (1983); Weitkamp (1978); Weitkamp et al. (1966); Yang et al.
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John A. Phillips, III - updated: 1/16/2003
John A. Phillips, III - updated: 3/18/1999
Victor A. McKusick: 6/4/1986