Vitamin D–Binding Protein Deficiency and Homozygous Deletion of the <i>GC</i> Gene

Henderson, Clark M.; Fink, Susan L.; Bassyouni, Hanan; Argiropoulos, Bob; Brown, Lindsay; Laha, Thomas J.; Jackson, Konner J; Lewkonia, Ray; Ferreira, P; Hoofnagle, Andrew N.; Marcadier, Julien L.

doi:10.1056/nejmoa1807841

Cited by 54 publications

(48 citation statements)

References 24 publications

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“…In addition, these mice were more resistant to the toxic effect of exposure to high doses of vitamin D, probably by more rapid catabolism of vitamin D and its metabolites. In 2019, the first case of true total DBP deficiency was described in a 58-year old Canadian woman, with very low serum concentrations of 25OHD and 1,25(OH) 2 D and absence of serum DBP (all measured by gold standard technology of liquid chromatography-tandem mass spectrometry) (23). Nevertheless, no history of rickets or signs of osteomalacia were present and the patient had normal serum calcium and PTH concentrations.…”

Section: Functions Of Dbp (Table 2)mentioning

confidence: 99%

“…It is rather unlikely that this is related to the absence of DBP, as this phenotype is not found in DBP null mice. It may be related to the loss of the adjacent gene or due to repeated exposure to very high doses of vitamin D as to "correct her apparent vitamin D deficiency" although these interventions failed to increase serum vitamin D metabolites (23). Similarly, absence of albumin in humans is not causing a major phenotype.…”

Section: Functions Of Dbp (Table 2)mentioning

confidence: 99%

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Vitamin D Binding Protein: A Historic Overview

et al. 2020

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Vitamin D and all its metabolites are bound to a specific vitamin D binding protein, DBP. This protein was originally first discovered by its worldwide polymorphism and called Group-specific Component (GC). We now know that DBP and GC are the same protein and appeared early in the evolution of vertebrates. DBP is genetically the oldest member of the albuminoid family (including albumin, α-fetoprotein and afamin, all involved in transport of fatty acids or hormones). DBP has a single binding site for all vitamin D metabolites and has a high affinity for 25OHD and 1,25(OH)2D, thereby creating a large pool of circulating 25OHD, which prevents rapid vitamin D deficiency. DBP of higher vertebrates (not amphibians or reptiles) binds with very high affinity actin, thereby preventing the formation of polymeric actin fibrils in the circulation after tissue damage. Megalin is a cargo receptor and is together with cubilin needed to reabsorb DBP or the DBP-25OHD complex, thereby preventing the urinary loss of these proteins and 25OHD. The total concentrations of 25OHD and 1,25(OH)2D in DBP null mice or humans are extremely low but calcium and bone homeostasis remain normal. This is the strongest argument for claiming that the "free hormone hypothesis" also applies to the vitamin D hormone, 1,25(OH)2D. DBP also transports fatty acids, and can play a role in the immune system. DBP is genetically very polymorphic with three frequent alleles (DBP/GC 1f, 1s, and 2) but in total more than 120 different variants but its health consequences, if any, are not understood. A standardization of DBP assays is essential to further explore the role of DBP in physiology and diseases.

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Section: Functions Of Dbp (Table 2)mentioning

confidence: 99%

Section: Functions Of Dbp (Table 2)mentioning

confidence: 99%

Vitamin D Binding Protein: A Historic Overview

et al. 2020

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“…The serum DBP is responsible for the transport of all vitamin D metabolites due to its high affinity for all metabolites and especially for 25OHD. It thereby regulates the free concentration of these metabolites as is best demonstrated by the extremely low serum concentrations of 25OHD and 1,25(OH) 2 D in animals or the single human subject with bi‐allelic mutations in the DBP/GC gene . Up to now, most experts considered DBP as being stably expressed by hepatocytes with little or no regulation, apart from the stimulatory effects of estrogens .…”

Section: Vitamin D Binding Proteinmentioning

confidence: 99%

“…It thereby regulates the free concentration of these metabolites as is best demonstrated by the extremely low serum concentrations of 25OHD and 1,25(OH) 2 D in animals or the single human subject with bi-allelic mutations in the DBP/GC gene. (106) Up to now, most experts considered DBP as being stably expressed by hepatocytes with little or no regulation, apart from the stimulatory effects of estrogens. (107) DBP concentrations, however, are slightly (~10%) lower in homozygous DBP/GC2-2 carriers with a similar decrease in total 25OHD concentrations.…”

Section: Vitamin D Binding Proteinmentioning

confidence: 99%

Vitamin D Metabolism Revised: Fall of Dogmas

Bouillon

Bikle

2019

Journal of Bone and Mineral Research

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“…DBP is comprised of 3 structurally similar domains. The first domain is the binding site for the vitamin D metabolites (aa [35][36][37][38][39][40][41][42][43][44][45][46][47][48][49]. Fatty acid binding utilizes a single high affinity site for both palmitic acid and arachidonic acid, but only arachidonic acid competes with 25(OH)D for binding (16,17).…”

Section: Structure and Polymorphismsmentioning

confidence: 99%

Vitamin D Binding Protein, Total and Free Vitamin D Levels in Different Physiological and Pathophysiological Conditions

2020

Frontiers Research Topics

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This review focuses on the biologic importance of the vitamin D binding protein (DBP) with emphasis on its regulation of total and free vitamin D metabolite levels in various clinical conditions. Nearly all DBP is produced in the liver, where its regulation is influenced by estrogen, glucocorticoids and inflammatory cytokines but not by vitamin D itself. DBP is the most polymorphic protein known, and different DBP alleles can have substantial impact on its biologic functions. The three most common alleles-Gc1f, Gc1s, Gc2-differ in their affinity with the vitamin D metabolites and have been variably associated with a number of clinical conditions. Although DBP has a number of biologic functions independent of vitamin D, its major biologic function is that of regulating circulating free and total levels of vitamin D metabolites. 25 hydroxyvitamin D (25(OH)D) is the best studied form of vitamin D as it provides the best measure of vitamin D status. In a normal non-pregnant individual, approximately 0.03% of 25(OH)D is free; 85% is bound to DBP, 15% is bound to albumin. The free hormone hypothesis postulates that only free 25(OH)D can enter cells. This hypothesis is supported by the observation that mice lacking DBP, and therefore with essentially undetectable 25(OH)D levels, do not show signs of vitamin D deficiency unless put on a vitamin D deficient diet. Similar observations have recently been described in a family with a DBP mutation. This hypothesis also applies to other protein bound lipophilic hormones including glucocorticoids, sex steroids, and thyroid hormone. However, tissues expressing the megalin/cubilin complex, such as the kidney, have the capability of taking up 25(OH)D still bound to DBP, but most tissues rely on the free level. Attempts to calculate the free level using affinity constants generated in a normal individual along with measurement of DBP and total 25(OH)D have not accurately reflected directly measured free levels in a number of clinical conditions. In this review, we examine the impact of different clinical conditions as well as different DBP alleles on the relationship between total and free 25(OH)D, using only data in which the free 25(OH)D level was directly measured. The major conclusion is that a number of clinical conditions alter this relationship, raising the question whether measuring just total 25(OH)D might be misleading regarding the assessment of vitamin D status, and such assessment might be improved by measuring free 25(OH)D instead of or in addition to total 25(OH)D.Keywords: vitamin D binding protein, vitamin D, free 25(OH)D, free hormone hypothesis, megalin, polymorphisms, liver cirrhosis, pregnancy Bikle and Schwartz DBP and Free 25(OH)D

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Vitamin D–Binding Protein Deficiency and Homozygous Deletion of the GC Gene

Cited by 54 publications

References 24 publications

Vitamin D Binding Protein: A Historic Overview

Vitamin D Binding Protein: A Historic Overview

Vitamin D Metabolism Revised: Fall of Dogmas

Vitamin D Binding Protein, Total and Free Vitamin D Levels in Different Physiological and Pathophysiological Conditions

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