<i>CYP2R1</i>Mutations Impair Generation of 25-hydroxyvitamin D and Cause an Atypical Form of Vitamin D Deficiency

Thacher, Tom D.; Fischer, Philip R.; Singh, Ravinder J.; Roizen, Jeffrey D.; Levine, Michael A.

doi:10.1210/jc.2015-1746

Cited by 106 publications

(68 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Studies conducted in humans have shown that CYP2R1 is a good candidate for the enzymatic conversion of vitamin D3 to 25(OH)D3, since patients with a mutation in CYP2R1 have a deficiency of 25(OH)D3 and exhibit signs and symptoms of vitamin D deficiency and develop rickets [147, 148]. In animals, CYP2R1 has also been shown to be the main enzyme responsible for 25-hydroxylation of vitamin D [172].…”

Section: Hormonal Factors That Affect Pi Balancementioning

confidence: 99%

Physiological regulation of phosphate by vitamin D, parathyroid hormone (PTH) and phosphate (Pi)

Jacquillet

Unwin

2018

Pflugers Arch - Eur J Physiol

119

View full text Add to dashboard Cite

Inorganic phosphate (Pi) is an abundant element in the body and is essential for a wide variety of key biological processes. It plays an essential role in cellular energy metabolism and cell signalling, e.g. adenosine and guanosine triphosphates (ATP, GTP), and in the composition of phospholipid membranes and bone, and is an integral part of DNA and RNA. It is an important buffer in blood and urine and contributes to normal acid-base balance. Given its widespread role in almost every molecular and cellular function, changes in serum Pi levels and balance can have important and untoward effects. Pi homoeostasis is maintained by a counterbalance between dietary Pi absorption by the gut, mobilisation from bone and renal excretion. Approximately 85% of total body Pi is present in bone and only 1% is present as free Pi in extracellular fluids. In humans, extracellular concentrations of inorganic Pi vary between 0.8 and 1.2 mM, and in plasma or serum Pi exists in both its monovalent and divalent forms (H2PO4− and HPO42−). In the intestine, approximately 30% of Pi absorption is vitamin D regulated and dependent. To help maintain Pi balance, reabsorption of filtered Pi along the renal proximal tubule (PT) is via the NaPi-IIa and NaPi-IIc Na+-coupled Pi cotransporters, with a smaller contribution from the PiT-2 transporters. Endocrine factors, including, vitamin D and parathyroid hormone (PTH), as well as newer factors such as fibroblast growth factor (FGF)-23 and its coreceptor α-klotho, are intimately involved in the control of Pi homeostasis. A tight regulation of Pi is critical, since hyperphosphataemia is associated with increased cardiovascular morbidity in chronic kidney disease (CKD) and hypophosphataemia with rickets and growth retardation. This short review considers the control of Pi balance by vitamin D, PTH and Pi itself, with an emphasis on the insights gained from human genetic disorders and genetically modified mouse models.

show abstract

Section: Hormonal Factors That Affect Pi Balancementioning

confidence: 99%

Physiological regulation of phosphate by vitamin D, parathyroid hormone (PTH) and phosphate (Pi)

Jacquillet

Unwin

2018

Pflugers Arch - Eur J Physiol

119

View full text Add to dashboard Cite

show abstract

“…Analysis of 1,25-dihydroxyvitamin D degradative activity of WT and mutant CYP3A4 recombinant proteins was performed using a mammalian 2-hybrid expression system in which activity of firefly luciferase is proportional to the concentration of intracellular 1,25-dihydroxyvitamin D (see Supplemental Methods and ref. 4). Activity against other substrates was assayed by measuring CYP3A4 conversion of luciferin IPA to the luminescent luciferin.…”

Section: Increased Activity Of Cyp3a4 Pi301t In Transfected Cells Ismentioning

confidence: 99%

“…Vitamin D is biologically inactive and undergoes 2 enzymatic conversions to become fully active 1,25-dihydroxyvitamin D. The existence of rickets in areas with abundant sunlight has led to the identification of genetic forms of vitamin D-dependent rickets (VDDRs). Type 1 VDDRs are caused by defects in vitamin D activation, owing to mutations in the genes encoding either the renal 1-α hydroxylase (CYP27B1: VDDR-1A) (2) or the hepatic 25-hydroxylase (CYP2R1: VDDR-1B) (3,4). Type 2 VDDRs are caused by defects in vitamin D receptor signaling due to mutations in the gene encoding the vitamin D receptor (VDR: VDDR-2A); or heterogeneous nuclear ribonucleoprotein C (HNRNPC: VDDR-2B) (5,6), a VDR coactivator.…”

Section: Introductionmentioning

confidence: 99%

CYP3A4 mutation causes vitamin D–dependent rickets type 3

Roizen

Liu

O'Lear

et al. 2018

Journal of Clinical Investigation

Self Cite

View full text Add to dashboard Cite

“…Defects in 25‐ or 1α‐hydroxylation lead to an inability to activate vitamin D, thus causing a vitamin D deficiency–like state that is resistant to physiologic doses of vitamin D. Vitamin D–dependent rickets type 1A (VDDR1A, MIM 264700) was first described and associated with loss‐of‐function mutations of CYP27B1 . Mutations of CYP2R1 have recently been associated with VDDR1B (MIM 600081), a very rare condition that has been reported to currently affect only 4 families …”

Section: Introductionmentioning

confidence: 99%

“…Mutations of CYP2R1 have recently been associated with VDDR1B (MIM 600081), a very rare condition that has been reported to currently affect only 4 families. (1)(2)(3)(4)(5) In this article, we described the molecular analysis of 7 patients from 2 unrelated families who presented with VDDR1B due to a loss-of-function mutation of CYP2R1 and a new mutation. We noted the specific biochemical pattern of the disease and its dramatic improvement with 25-hydroxyvitamin D therapy.…”

Section: Introductionmentioning

confidence: 99%

Vitamin D–Dependent Rickets Type 1B (25-Hydroxylase Deficiency): A Rare Condition or a Misdiagnosed Condition?

Molin

Wiedemann

Demers

et al. 2017

Journal of Bone and Mineral Research

View full text Add to dashboard Cite

Vitamin D requires a two-step activation by hydroxylation: The first step is catalyzed by hepatic 25-hydroxylase (CYP2R1, 11p15.2) and the second one is catalyzed by renal 1α-hydroxylase (CYP27B1, 12q13.1), which produces the active hormonal form of 1,25-(OH) D. Mutations of CYP2R1 have been associated with vitamin D-dependent rickets type 1B (VDDR1B), a very rare condition that has only been reported to affect 4 families to date. We describe 7 patients from 2 unrelated families who presented with homozygous loss-of-function mutations of CYP2R1. Heterozygous mutations were present in their normal parents. We identified a new c.124_138delinsCGG (p.Gly42_Leu46delinsArg) variation and the previously published c.296T>C (p.Leu99Pro) mutation. Functional in vitro studies confirmed loss-of-function enzymatic activity in both cases. We discuss the difficulties in establishing the correct diagnosis and the specific biochemical pattern, namely, very low 25-OH-D suggestive of classical vitamin D deficiency, in the face of normal/high concentrations of 1,25-(OH) D. Siblings exhibited the three stages of rickets based on biochemical and radiographic findings. Interestingly, adult patients were able to maintain normal mineral metabolism without vitamin D supplementation. One index case presented with a partial improvement with 1alfa-hydroxyvitamin D or alfacalcidol (1α-OH-D ) treatment, and we observed a dramatic increase in the 1,25-(OH) D serum concentration, which indicated the role of accessory 25-hydroxylase enzymes. Lastly, in patients who received calcifediol (25-OH-D ), we documented normal 24-hydroxylase activity (CYP24A1). For the first time, and according to the concept of personalized medicine, we demonstrate dramatic improvements in patients who were given 25-OH-D therapy (clinical symptoms, biochemical data, and bone densitometry). In conclusion, the current study further expands the CYP2R1 mutation spectrum. We note that VDDR1B could be easily mistaken for classical vitamin D deficiency. © 2017 American Society for Bone and Mineral Research.

show abstract

CYP2R1Mutations Impair Generation of 25-hydroxyvitamin D and Cause an Atypical Form of Vitamin D Deficiency

Abstract: These studies confirm that CYP2R1 is the principal 25-hydroxylase in humans and demonstrate that CYP2R1 alleles have dosage-dependent effects on vitamin D homeostasis. CYP2R1 mutations cause a novel form of genetic vitamin D deficiency with semidominant inheritance.

Cited by 106 publications

References 56 publications

Physiological regulation of phosphate by vitamin D, parathyroid hormone (PTH) and phosphate (Pi)

Physiological regulation of phosphate by vitamin D, parathyroid hormone (PTH) and phosphate (Pi)

CYP3A4 mutation causes vitamin D–dependent rickets type 3

Vitamin D–Dependent Rickets Type 1B (25-Hydroxylase Deficiency): A Rare Condition or a Misdiagnosed Condition?

Contact Info

Product

Resources

About