Mutation of the CYP2R1 Vitamin D 25-Hydroxylase in a Saudi Arabian Family with Severe Vitamin D Deficiency

Context: Inherited forms of vitamin D deficiency are rare causes of rickets and to date have been traced to mutations in three genes, VDR, encoding the 1 alpha,25-dihydroxyvitamin D receptor, CYP27B1, encoding the vitamin D 1 alpha-hydroxylase, and CYP2R1, encoding a microsomal vitamin D 25-hydroxylase. Results: Multiple mutations have been identified in VDR and CYP27B1 in patients with rickets, and thus, the roles of these two genes in vitamin D metabolism are unassailable. The case is less clear for CYP2R1, in which only a single mutation, L99P in exon 2 of the gene, has been identified in Nigerian families, and because multiple enzymes with vitamin D 25-hydroxylase activity have been identified. Here we report molecular genetic studies on two siblings from a Saudi family who presented with classic symptoms of vitamin D deficiency. The affected offspring inherited two different CYP2R1 mutations (367 + 1, G -> A; 768, iT), which are predicted to specify null alleles. Conclusion: We conclude that CYP2R1 is a major vitamin D 25-hydroxylase that plays a fundamental role in activation of this essential vitamin. (J Clin Endocrinol Metab 97: E2022-E2025, 2012)