Review
Biological and clinical aspects of the vitamin D binding protein (Gc-globulin) and its polymorphism

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Abstract

The vitamin D binding protein (DBP) is the major plasma carrier protein of vitamin D and its metabolites. Unlike other hydrophobic hormone-binding systems, it circulates in a considerably higher titer compared to its ligands. Apart from its specific sterol binding capacity, DBP exerts several other important biological functions such as actin scavenging, fatty acid transport, macrophage activation and chemotaxis.

The DBP-gene is a member of a multigene cluster that includes albumin, α-fetoprotein, and α-albumin/afamin. All four genes are expressed predominantly in the liver with overlapping developmental profiles.

DBP is a highly polymorphic serum protein with three common alleles (Gc1F, Gc1S and Gc2) and more than 120 rare variants. The presence of unique alleles is a useful tool for anthropological studies to discriminate and to reveal ancestral links between populations.

Many studies have discussed the link between DBP-phenotypes and susceptibility or resistance to osteoporosis, Graves' disease, Hashimoto's thyroiditis, diabetes, COPD, AIDS, multiple sclerosis, sarcoidosis and rheumatic fever.

This article reviews the general characteristics, functions and clinical aspects of DBP.

Introduction

The vitamin D binding protein (DBP), formerly known as group-specific component of serum (Gc-globulin), is the major plasma carrier protein of vitamin D and its metabolites. Vitamin D sterols are necessary to maintain a normal serum calcium concentration and electrolyte homeostasis.

DBP is a member of the albumin, α-fetoprotein and α-albumin/afamin gene family. It is a highly polymorphic serum protein, predominantly synthesized in the liver as a single chain of glycoproteins with a molecular weight of 52–59 kDa. Apart from its specific sterol binding capacity, DBP exerts several other important biological functions, from actin scavenging to fatty acid transport and macrophage activation. DBP is involved in macrophage chemotaxis and may play a role in bone density. In this review, biological and clinical aspects of DBP will be discussed. Special interest has risen in the use of DBP as a marker for trauma, based on the actin scavenging properties of DBP.

Section snippets

Structure, synthesis, turnover

DBP is a serum α2-globulin with a molecular weight of 52–59 kDa [1], [2]. The human DBP-gene is localized on the long arm of chromosome 4 (4q12–q13) (Fig. 1). It extends over 35 kb DNA and contains 13 exons and 12 introns. The amino acid sequence is composed of 458 amino acids, arranged in three domains, in addition to a 16 amino acid leader sequence [1], [3], [4]. Two binding regions have been identified within the DBP-sequence: a vitamin D binding domain between residues 35 and 49 and an

Vitamin D binding

The major function of DBP is binding, solubilization and transport of vitamin D and its metabolites [25]. Each DBP-vitamin D metabolite complex has its own affinity constant. 25(OH)-vitamin D3 (calcidiol) binds DBP (88% bound) with high affinity (Ka = 5 × 10 8 M), whereas 1,25(OH)2-vitamin D3 (calcitriol), the most active metabolite of vitamin D, is bound (85%) with a lower affinity (Ka = 4 × 10 7 M) [5]. Unlike other hydrophobic hormone-carrier proteins in human plasma, DBP has a high plasma

Clinical aspects

Many researchers have made attempts to link the expression of the DBP-alleles with susceptibility or resistance to disease.

Conclusion

DBP has recently received increasing attention. DBP is recognized as a member of a multigene family that includes albumin, α-fetoprotein and α-albumin/afamin. This highly polymorphic serum protein exhibits a geographical distribution with several exotic alleles, resulting in numerous phenotypes.

DBP is synthesized in liver as a single polypeptide and exhibits multifunctional properties. Besides the transport of vitamin D-metabolites, DBP binds G-actin with high-affinity and sequesters monomeric

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