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Presence of a Deletion Mutation (c.716delA) in the Ligand Binding Domain of the Vitamin D Receptor in an Indian Patient with Vitamin D-Dependent Rickets Type II

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Abstract

Vitamin D-dependent rickets type II (VDDR-type II) is a rare disorder caused by mutations in the vitamin D receptor (VDR) gene. Here, we describe a patient with VDDR-type II with severe alopecia and rickets. She had hypocalcemia, hypophosphatemia, secondary hyperparathyroidism, and elevated serum alkaline phosphatase and 1,25-dihydroxyvitamin D3. Sequence analysis of the lymphocyte VDR cDNA revealed deletion mutation c.716delA. Sequence analysis of her genomic DNA fragment amplified from exon 6 of the VDR gene incorporating this mutation confirmed the presence of the mutation in homozygous form. This frameshift mutation in the ligand binding domain (LBD) resulted in premature termination (p.Lys240Argfs) of the VDR protein. The mutant protein contained 246 amino acids, with 239 normal amino acids at the N terminus, followed by seven changed amino acids resulting in complete loss of its LBD. The mutant VDR protein showed evidence of 50% reduced binding with VDR response elements on electrophoretic mobility assay in comparison to the wild-type VDR protein. She was treated with high-dose calcium infusion and oral phosphate. After 18 months of treatment, she gained 6 cm of height, serum calcium and phosphorus improved, alkaline phosphatase levels decreased, and intact PTH normalized. Radiologically, there were signs of healing of rickets. Her parents and one of her siblings had the same c.716delA mutation in heterozygous form. Despite the complete absence of LBD, the rickets showed signs of healing with intravenous calcium.

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Acknowledgments

The authors acknowledge the financial help from the Indian Council of Medical Research to N. T. during his senior research fellowship and the help of Dr. Achouba Singh, Senior Resident in the Department of Endocrinology, in the medical management and follow-up of the patient.

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Authors and Affiliations

  1. Department of Endocrinology and Metabolism, All India Institute of Medical Sciences, New Delhi, 110029, India

    Jeyaraman Kanakamani, Neeraj Tomar, Esha Kaushal, Nikhil Tandon & Ravinder Goswami

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  1. Jeyaraman Kanakamani
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  2. Neeraj Tomar
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  3. Esha Kaushal
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  5. Ravinder Goswami
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Correspondence to Ravinder Goswami.

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Jeyaraman Kanakamani and Neeraj Tomar contributed equally to this work.

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Kanakamani, J., Tomar, N., Kaushal, E. et al. Presence of a Deletion Mutation (c.716delA) in the Ligand Binding Domain of the Vitamin D Receptor in an Indian Patient with Vitamin D-Dependent Rickets Type II. Calcif Tissue Int 86, 33–41 (2010). https://doi.org/10.1007/s00223-009-9310-2

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  • DOI: https://doi.org/10.1007/s00223-009-9310-2

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