title: Hereditary vitamin D resistant rickets: identification of a novel splice site mutation in the vitamin D receptor gene and successful treatment with oral calcium therapy.
abstract: OBJECTIVE
  To study the vitamin D receptor (VDR) gene in a young girl with severe rickets and clinical features of hereditary vitamin D resistant rickets, including hypocalcemia, hypophosphatemia, partial alopecia, and elevated serum levels of 1,25-dihydroxyvitamin D.
  
  
  METHODS
  We amplified and sequenced DNA samples from blood from the patient, her mother, and the patient's two siblings. We also amplified and sequenced the VDR cDNA from RNA isolated from the patient's blood.
  
  
  RESULTS
  DNA sequence analyses of the VDR gene showed that the patient was homozygous for a novel guanine to thymine substitution in the 5'-splice site in the exon 8-intron J junction. Analysis of the VDR cDNA using reverse transcriptase-polymerase chain reaction showed that exons 7 and 9 were fused, and that exon 8 was skipped. The mother was heterozygous for the mutation and the two siblings were unaffected.
  
  
  CONCLUSIONS
  A novel splice site mutation was identified in the VDR gene that caused exon 8 to be skipped. The mutation deleted amino acids 303-341 in the VDR ligand-binding domain, which is expected to render the VDR non-functional. Nevertheless, successful outpatient treatment was achieved with frequent high doses of oral calcium.
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Pediatrics, Childrens Hospital Los Angeles and Keck School of Medicine of the University of Southern California, Los Angeles, CA 90027, USA. nma@alum.mit.edu
authors.forename: Nina S
authors.initials: NS
authors.lastname: Ma
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Malloy
authors.forename: Pisit
authors.initials: P
authors.lastname: Pitukcheewanont
authors.forename: Daina
authors.initials: D
authors.lastname: Dreimane
authors.forename: Mitchell E
authors.initials: ME
authors.lastname: Geffner
authors.forename: David
authors.initials: D
authors.lastname: Feldman
mesh_terms: D000284:Administration, Oral; D000595:Amino Acid Sequence; D001483:Base Sequence; D002118:Calcium / Q000008:administration & dosage* / Q000627:therapeutic use*; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000235:genetics; D005091:Exons / Q000235:genetics; D053098:Familial Hypophosphatemic Rickets / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000235:genetics*; D005260:Female; D006760:Hospitalization; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D011247:Pregnancy; D022821:RNA Splice Sites / Q000235:genetics*; D011859:Radiography; D018167:Receptors, Calcitriol / Q000737:chemistry / Q000235:genetics*
chemical_list: D018076:DNA, Complementary; D022821:RNA Splice Sites; D018167:Receptors, Calcitriol; D002118:Calcium