Novel Compound Heterozygous Mutations in the CYP27B1 Gene Lead to Pseudovitamin D-Deficient Rickets

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• 作者：W. Nadia H. Koek ; M. Carola Zillikens…
• 刊名：Calcified Tissue International
• 出版年：2016
• 出版时间：September 2016
• 年：2016
• 卷：99
• 期：3
• 页码：326-331
• 全文大小：474 KB
• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Life Sciences
  Biochemistry
  Endocrinology
  Orthopedics
  Cell Biology
  
• 出版者：Springer New York
• ISSN：1432-0827
• 卷排序：99

文摘

Pseudovitamin D deficiency is the consequence of a genetic defect in the CYP27B1 gene resulting in diminished or absent conversion of 25-hydroxyvitamin D₃ (25-(OH)D₃) into 1,25-dihydroxyvitamin D₃ (1,25-(OH)₂D₃) and leads to growth retardation and rickets, usually in the first 2 years of life. DNA obtained from human leucocytes from a patient suspected of pseudovitamin D deficiency and her healthy parents was sequenced for a genetic defect in the CYP27B1 gene. In silico analyses on the mutations were performed using online available software. The 1α-hydroxylase activity of the patient, her parents, and a sample derived from a mixed buffy coat of healthy blood donors was measured by culturing peripheral blood mononuclear cells with 25-(OH)D₃ and measuring 1,25-(OH)₂D₃ production. DNA sequencing of the patient suspected of pseudovitamin D deficiency revealed compound heterozygosity in the CYP27B1 gene for a (c413G>T) mutation in exon 3 (R138L) and a (c1232G>A) mutation in exon 8 (C411Y). In silico analyses confirmed that mutations at these positions are probably damaging for the protein since the amino acids are situated in a highly conserved region. In vitro analyses showed a nearly absent 1α-hydroxylase activity in the patient compared to the healthy blood donors. Her healthy parents each of whom carried one of the mutations also had compromised conversion of 25-(OH)D₃ into 1,25-(OH)₂D₃ in peripheral blood mononuclear cells, being only marginally higher than in the patient. We discovered novel compound heterozygous mutations in the CYP27B1 gene in a young girl presenting with pseudovitamin D-deficient rickets, leading to severely decreased 1,25-(OH)₂D₃ production. Furthermore, both heterozygous parents showed a diminished 1α-hydroxylase activity.Keywords1α-hydroxylasePeripheral blood mononuclear cellsCYP27B1 pseudovitamin D deficiency