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The  CYP27B1  gene encodes 25-hydroxyvitamin D-1α-hydroxylase. Mutations of this gene cause vitamin D-dependent rickets type 1A (VDDR-IA, OMIM 264700), which is a rare autosomal recessive disorder. To investigate  CYP27B1  mutations, we studied 8 patients from 7 unrelated families. All coding exons and intron-exon boundaries of  CYP27B1  gene were amplified by PCR from peripheral leukocyte DNA and subsequently sequenced. Homozygous mutations in the  CYP27B1  gene were found in all the patients and heterozygous mutations were present in their normal parents. One novel single nucleotide variation (SNV, c.1215 T>C, p.R379R in the last nucleotide of exon 7) and three novel mutations were identified:, a splice donor site mutation (c.1215+2T>A) in intron 7, a 16-bp deletion in exon 6 (c.1022-1037del16), and a 2-bp deletion in exon 5 (c.934_935delAC). Both c.1215 T>C and c.1215+2T>A were present together in homozygous form in two unrelated patients, and caused exon 7 skipping. However, c.1215 T>C alone has no effect on pre-mRNA splicing. The skipping of exon 7 resulted in a shift of downstream reading frame and a premature stop codon 57 amino acids from L380 (p.L380Afs*57). The intra-exon deletions of c.1022-1037del16 and c.934_935delAC also resulted in a frameshift and the creation of premature stop codons at p.T341Rfs*5, and p.T312Rfs*19, respectively, leading to the functional inactivation of the  CYP27B1  gene. Clinically, all the patients required continued calcitriol treatment and the clinical presentations were consistent with the complete loss of vitamin D1α-hydroxylase activity. In conclusion, three novel mutations have been identified. All of them caused frameshift and truncated proteins. The silent c.1215 T>C SNV has no effect on pre-mRNA splicing and it is likely a novel SNP. The current study further expands the  CYP27B1  mutation spectrum.

Novel CYP27B1 Gene Mutations in Patients with Vitamin D-Dependent Rickets Type 1A