title: 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.
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 D(3). 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.
authors.affiliation: Department of Endocrinology and Metabolism, All India Institute of Medical Sciences, New Delhi 110029, India. kanakamani@rediffmail.com
authors.forename: Jeyaraman
authors.initials: J
authors.lastname: Kanakamani
authors.forename: Neeraj
authors.initials: N
authors.lastname: Tomar
authors.forename: Esha
authors.initials: E
authors.lastname: Kaushal
authors.forename: Nikhil
authors.initials: N
authors.lastname: Tandon
authors.forename: Ravinder
authors.initials: R
authors.lastname: Goswami
mesh_terms: D000293:Adolescent; D000469:Alkaline Phosphatase / Q000097:blood; D000505:Alopecia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D000595:Amino Acid Sequence / Q000235:genetics; D001483:Base Sequence; D002117:Calcitriol / Q000097:blood; D002118:Calcium / Q000494:pharmacology / Q000627:therapeutic use; D018389:Codon, Nonsense / Q000235:genetics; D004252:DNA Mutational Analysis; D053098:Familial Hypophosphatemic Rickets / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics; D017353:Gene Deletion; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D006961:Hyperparathyroidism / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D006996:Hypocalcemia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D017674:Hypophosphatemia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D009154:Mutation / Q000235:genetics*; D010710:Phosphates / Q000494:pharmacology / Q000627:therapeutic use; D017434:Protein Structure, Tertiary / Q000235:genetics; D018167:Receptors, Calcitriol / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D020127:Recovery of Function / Q000502:physiology; D016896:Treatment Outcome
chemical_list: D018389:Codon, Nonsense; D005819:Genetic Markers; D010710:Phosphates; D018167:Receptors, Calcitriol; D000469:Alkaline Phosphatase; D002117:Calcitriol; D002118:Calcium