CYP2R1 Mutations Impair Generation of 25-hydroxyvitamin D and Cause an Atypical Form of Vitamin D Deficiency.
BACKGROUND
Production of the active vitamin D hormone 1,25-dihydroxyvitamin D requires hepatic 25-hydroxylation of vitamin D. The CYP2R1 gene encodes the principal vitamin D 25-hydroxylase in humans.


OBJECTIVE
This study aimed to determine the prevalence of CYP2R1 mutations in Nigerian children with familial rickets and vitamin D deficiency and assess the functional effect on 25-hydroxylase activity.


METHODS
We sequenced the CYP2R1 gene in subjects with sporadic rickets and affected subjects from families in which more than one member had rickets.


METHODS
Function of mutant CYP2R1 genes as assessed in vivo by serum 25-hydroxyvitamin D values after administration of vitamin D and in vitro by analysis of mutant forms of the CYP2R1.


RESULTS
CYP2R1 sequences were normal in 27 children with sporadic rickets, but missense mutations were identified in affected members of 2 of 12 families, a previously identified L99P, and a novel K242N. In silico analyses predicted that both substitutions would have deleterious effects on the variant proteins, and in vitro studies showed that K242N and L99P had markedly reduced or complete loss of 25-hydroxylase activity, respectively. Heterozygous subjects were less affected than homozygous subjects, and oral administration of vitamin D led to significantly lower increases in serum 25-hydroxyvitamin D in heterozygous than in control subjects, whereas homozygous subjects showed negligible increases.


CONCLUSIONS
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.
Department of Family Medicine (T.D.T.), Jos University Teaching Hospital, Jos, Nigeria 930241; Department of Family Medicine (T.D.T.), Department of Pediatric and Adolescent Medicine (P.R.F.), and Department of Laboratory Medicine and Pathology (R.J.S.), Mayo Clinic, Rochester, Minnesota 55905; and The Children's Hospital of Philadelphia and Department of Pediatrics (J.R., M.A.L.), University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104.
Tom D
TD
Thacher
Department of Family Medicine (T.D.T.), Jos University Teaching Hospital, Jos, Nigeria 930241; Department of Family Medicine (T.D.T.), Department of Pediatric and Adolescent Medicine (P.R.F.), and Department of Laboratory Medicine and Pathology (R.J.S.), Mayo Clinic, Rochester, Minnesota 55905; and The Children's Hospital of Philadelphia and Department of Pediatrics (J.R., M.A.L.), University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104.
Philip R
PR
Fischer
Department of Family Medicine (T.D.T.), Jos University Teaching Hospital, Jos, Nigeria 930241; Department of Family Medicine (T.D.T.), Department of Pediatric and Adolescent Medicine (P.R.F.), and Department of Laboratory Medicine and Pathology (R.J.S.), Mayo Clinic, Rochester, Minnesota 55905; and The Children's Hospital of Philadelphia and Department of Pediatrics (J.R., M.A.L.), University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104.
Ravinder J
RJ
Singh
Department of Family Medicine (T.D.T.), Jos University Teaching Hospital, Jos, Nigeria 930241; Department of Family Medicine (T.D.T.), Department of Pediatric and Adolescent Medicine (P.R.F.), and Department of Laboratory Medicine and Pathology (R.J.S.), Mayo Clinic, Rochester, Minnesota 55905; and The Children's Hospital of Philadelphia and Department of Pediatrics (J.R., M.A.L.), University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104.
Jeffrey
J
Roizen
Department of Family Medicine (T.D.T.), Jos University Teaching Hospital, Jos, Nigeria 930241; Department of Family Medicine (T.D.T.), Department of Pediatric and Adolescent Medicine (P.R.F.), and Department of Laboratory Medicine and Pathology (R.J.S.), Mayo Clinic, Rochester, Minnesota 55905; and The Children's Hospital of Philadelphia and Department of Pediatrics (J.R., M.A.L.), University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104.
Michael A
MA
Levine
D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D053493:Cholestanetriol 26-Monooxygenase / Q000235:genetics*; D015331:Cohort Studies; D000072467:Cytochrome P450 Family 2; D005190:Family; D006801:Humans; D007223:Infant; D008875:Middle Aged; D020125:Mutation, Missense; D009549:Nigeria / Q000453:epidemiology; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D012279:Rickets / Q000453:epidemiology / Q000235:genetics*; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000096:biosynthesis; D014808:Vitamin D Deficiency / Q000453:epidemiology / Q000235:genetics*; D055815:Young Adult
D014807:Vitamin D; C104450:25-hydroxyvitamin D; D000072467:Cytochrome P450 Family 2; C506833:CYP2R1 protein, human; D053493:Cholestanetriol 26-Monooxygenase