Protein chemical characterization of Gc globulin (vitamin D-binding protein) isoforms; Gc-1f, Gc-1s and Gc-2

Christiansen, M.; Jørgensen, Charlotte Sværke; Laursen, Inga; Hirschberg, Daniel; Højrup, Peter; Houen, Gunnar

doi:10.1016/j.bbapap.2007.01.005

Cited by 34 publications

(27 citation statements)

References 77 publications

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“…GC-1f is a combination of aspartic acid at position 432 and threonine at 436; GC-1s has a combination of glutamic acid at position 432 and threonine at 436, and GC-2 has a combination of aspartic acid at position 432 and lysine at 436 [9,10,11]. Previous research indicates that these differences in amino acid sequence are associated with variations in DBP affinity for 25(OH)D, with GC-1f having the highest, GC-1s having intermediate and GC-2 having the lowest affinity for 25(OH)D [10,11,27,28].…”

Section: Discussionmentioning

confidence: 99%

“…There are two well-studied missense single nucleotide polymorphisms (SNPs) in the GC gene: rs4588 (T436K), which causes a C-to-A transversion [threonine (ACG) to a lysine (AAG)], and rs7041 (D432E), which causes a T-to-G transversion [an aspartic acid (GAT) to a glutamic acid (GAG)]. The combination of these two SNPs is the molecular basis for the three major isoforms of DBP serum, namely GC-1f (wild type), GC-1s, and GC-2 [9,10,11]. These variants have been previously shown to be strongly associated with circulating 25-hydroxyvitamin D [25(OH)D] in genome-wide association studies [12,13] and in diverse populations [14,15,16,17,18].…”

Section: Introductionmentioning

confidence: 99%

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Variations in the Vitamin D-Binding Protein (DBP) Gene Are Related to Lower 25-Hydroxyvitamin D Levels in Healthy Girls: A Cross-Sectional Study

Santos¹,

Mascarenhas²,

Boguszewski³

et al. 2013

Horm Res Paediatr

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Background/Aims: Vitamin D deficiency has been recognized as a worldwide epidemic affecting several pediatric and adolescent populations. We determined the genotype and haplotype distribution of the rs4588 and rs7041 polymorphisms of the GC gene encoding vitamin D-binding protein (DBP)and investigated the associations between these gene variants and their haplotypes with 25-hydroxyvitamin D [25(OH)D] levels in girls from South Brazil. Methods: Cross-sectional study including 198 apparently healthy girls aged 10-18 years. Plasma levels of 25(OH)D were assessed by radioimmunoassay. Participants were genotyped for rs4588 and rs7041 by real-time PCR, with allelic discrimination assays. Results: Mean chronological age and BMI percentile were 13.17 ± 1.74 years and 57.81 ± 29.03, respectively. Sufficient circulating 25(OH)D levels (≥30 ng/ml) were found in 9.1% of the overall group, insufficient levels (20-29.9 ng/ml) in 59.6%, and deficient levels (<20 ng/ml) in 31.3%. The AA genotype of rs4588, TT genotype of rs7041 and CT-AT/AT-AT (GC 1f-2/2-2) diplotypes were significantly associated with lower 25(OH)D levels, even after adjustment for age and season at the time of blood collection. Conclusions: The GC gene genotype may be related to the susceptibility to low 25(OH)D levels in female children and adolescents.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Variations in the Vitamin D-Binding Protein (DBP) Gene Are Related to Lower 25-Hydroxyvitamin D Levels in Healthy Girls: A Cross-Sectional Study

Santos¹,

Mascarenhas²,

Boguszewski³

et al. 2013

Horm Res Paediatr

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“…VDBP, originally called group-specific component (Gc), has three major phenotypic variants characterized by isoelectric focusing electrophoresis: Gc1F(fast), Gc1S(slow), and Gc2 (36). Variation in the two most common polymorphisms in the VDBP gene (GC), rs4588 (A vs. C, resulting in lysine vs. threonine at position 420) and rs7041 (T vs. G, resulting in aspartic acid vs. glutamate at position 416), produce the three major GC haplotypes (GC1F, GC1S, and GC2).…”

Section: Low Serum Concentrations Of Total 25-hydroxyvitamin D (25[oh]d)mentioning

confidence: 99%

Critically Ill Children Have Low Vitamin D Binding Protein, Influencing Bioavailability of Vitamin D

Madden¹,

Feldman²,

Chun³

et al. 2015

Annals ATS

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Rationale: Vitamin D deficiency, often defined by total serum 25-hydroxyvitamin D (25[OH]D) ,20 ng/ml, is common in critically ill patients, with associations with increased mortality and morbidity in the intensive care unit. Correction of vitamin D deficiency in critical illness has been recommended, and ongoing clinical trials are investigating the effect of repletion on patient outcome. The biologically active amount of 25(OH)D depends on the concentration and protein isoform of vitamin D-binding protein (VDBP), which is also an acutephase reactant affected by inflammation and injury.Objectives: We performed a secondary analysis of a cohort of critically ill children in which we reported a high rate of vitamin D deficiency, to examine how VDBP level and genotype would impact vitamin D status. Methods:We prospectively enrolled 511 children admitted to the pediatric intensive care unit over a 12-month period. Measurements and Main Results:We measured serum VDBP in 479 children. We genotyped single nucleotide polymorphisms rs7041 and rs4588 in the VDBP gene (GC) to determine haplotypes GC1F, GC1S, and GC2 in 178 subjects who consented, then calculated bioavailable 25(OH)D from serum 25(OH)D, VDBP, albumin, and GC haplotype. The median serum VDBP level was 159 mg/ml (interquartile range, 108-221), lower than has been reported in healthy children. Factors predicting lower levels in multivariate analysis included age ,1 year, nonwhite race, being previously healthy, 25(OH)D ,20 ng/ml and greater illness severity. In the subgroup that was genotyped, GC haplotype had the strongest association with VDBP level; carriage of one additional copy of GC1S was associated with a 37.5% higher level (95% confidence interval, 31.9-44.8; P , 0.001). Bioavailable 25(OH)D was also inversely associated with illness severity (r = 20.24, P , 0.001), and ratio to measured total 25(OH)D was variable and related to haplotype.Conclusions: Physiologic deficiency of 25(OH)D in critical illness may be more difficult to diagnose, given that lower VDBP levels increase bioavailability. Treatment studies conducted on the basis of total 25(OH)D level, without consideration of VDBP concentration and genotype, may increase the risk of falsely negative results.

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“…Purified human plasma Gc-globulin was prepared as described by Christiansen et al [14]. Actin was initially dissolved in purified water at a concentration of 3.44 mg/mL (80 mM) and kept as a stock solution.…”

Section: Sample Preparationmentioning

confidence: 99%

“…The three major isoforms are denoted Gc1S, Gc1F and Gc2 [12][13][14]. Gc1S and Gc1F are the predominant isoforms among Caucasians and the black population, respectively [15,16].…”

Section: Introductionmentioning

confidence: 99%

Affinity capillary electrophoresis for identification and investigation of human Gc‐globulin (vitamin D‐binding protein) and its isoforms interacting with G‐actin

2008

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A CE procedure was established for the nondenaturing separation and identification of the isoforms of the actin-binding human plasma protein Gc-globulin. To characterize interactions with globular actin (G-actin), a novel method was developed for the simultaneous qualitative assessment of the binding interaction between the three major isoforms of Gc-globulin and G-actin using pre-equilibrium affinity CE and UV detection. Evidence was found that some difference in binding affinity existed among the isoforms, although the quantification of this difference was not feasible by UV detection because of the high affinity nature of the binding. The difference in affinity appeared to be related to the pI of the isoforms; a high pI corresponding to a high affinity. For quantitative binding studies Gc-globulin was fluorescently labeled with 5-(and-6)-carboxyfluorescein, succinimidyl ester (CFSE). Data suggested that extensive labeling interfered with actin binding but with moderately labeled Gc-globulin it was possible to determine a dissociation constant of K(d) = 21 +/- 1 nM for the binding between labeled Gc-globulin and G-actin using pre-equilibrium affinity CE and LIF detection.

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Protein chemical characterization of Gc globulin (vitamin D-binding protein) isoforms; Gc-1f, Gc-1s and Gc-2

Cited by 34 publications

References 77 publications

Variations in the Vitamin D-Binding Protein (DBP) Gene Are Related to Lower 25-Hydroxyvitamin D Levels in Healthy Girls: A Cross-Sectional Study

Variations in the Vitamin D-Binding Protein (DBP) Gene Are Related to Lower 25-Hydroxyvitamin D Levels in Healthy Girls: A Cross-Sectional Study

Critically Ill Children Have Low Vitamin D Binding Protein, Influencing Bioavailability of Vitamin D

Affinity capillary electrophoresis for identification and investigation of human Gc‐globulin (vitamin D‐binding protein) and its isoforms interacting with G‐actin

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