A Novel G102E Mutation of CYP27B1 in a Large Family with Vitamin D-Dependent Rickets Type 1

Context: Mutations in the CYP27B1 gene, which encodes vitamin D 1 alpha-hydroxylase, are the genetic basis for vitamin D-dependent rickets type 1 (VDDR-I). Objective: The aim of this study was to investigate the CYP27B1 mutation in a large family with VDDR-I and characterize the genotype-phenotype correlation. Patients and Methods: The index patient was a 23-yr-old female who had a progressive form of rickets and growth retardation since the age of 9 months. Laboratory data showed hypocalcemia, low urine calcium, hypophosphatemia, high serum alkaline phosphatase, elevated PTH, and low serum 1,25-dihydroxyvitamin D-3. Her parents were healthy first-degree cousins, and two of her 12 siblings were affected with similar but milder rickets. Three other siblings were asymptomatic but had biochemical evidence of the disease. The entire coding region of the CYP27B1 gene was sequenced, and the mutation was characterized by functional studies. Results: We found a novel biallelic c.305G>A sequence variation at codon 102, changing amino acid from glycine to glutamic acid (G102E) in the patient and five affected siblings, whereas a monoallelic c.305G>A variation was present in the mother and five nonaffected siblings. This variation was not present in 100 population controls. Expression of this mutant in CHO cells revealed an 80% reduction in the 1 alpha-hydroxylase activity as compared to wild-type activity. Conclusions: A novel mutation in the CYP27B1 gene was found in patients with VDDR-I. This mutation resulted in a significant reduction in 1 alpha-hydroxylase activity. The residual enzymatic activity may account for the mild phenotype presentation in some affected members. (J Clin Endocrinol Metab 95: 4176-4183, 2010)