Vitamin D receptor mutations in patients with hereditary 1,25-dihydroxyvitamin D-resistant rickets.
BACKGROUND
Hereditary vitamin D resistant rickets (HVDRR), also known as vitamin D-dependent rickets type II, is an autosomal recessive disorder characterized by the early onset of rickets with hypocalcemia, secondary hyperparathyroidism and hypophosphatemia and is caused by mutations in the vitamin D receptor (VDR) gene. The human gene encoding the VDR is located on chromosome 12 and comprises eight coding exons and seven introns.
We analyzed the VDR gene of 5 previously unreported patients, two from Singapore and one each from Macedonia (former Yugoslav Republic), Saudi Arabia and Turkey. Each patient had clinical and radiographic features of rickets, hypocalcemia, and the 4 cases that had the measurement showed elevated serum concentrations of 1,25-dihydroxyvitamin D (1,25(OH)(2)D). Mutations were re-created in the WT VDR cDNA and examined for 1,25(OH)(2)D(3)-mediated transactivation in COS-7 monkey kidney cells.


RESULTS
Direct sequencing identified four novel mutations and two previously described mutations in the VDR gene. The novel mutations included a missense mutation in exon 3 causing the amino acid change C60W; a missense mutation in exon 4 causing the amino acid change D144N; a missense mutation in exon 7 causing the amino acid change N276Y; and a 2bp deletion in exon 3 5'-splice site (IVS3∆+4-5) leading to a premature stop.


CONCLUSIONS
These 4 unique mutations add to the previous 45 mutations identified in the VDR gene in patients with HVDRR.
Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
Peter J
PJ
Malloy
Department of Pediatric Nephrology, Clinic for Children's Diseases, University Children's Hospital, Medical School of Skopje, Skopje, Macedonia.
Velibor
V
Tasic
Department of Endocrinology, Children's Hospital of Michigan, Detroit, MI 48201, USA.
Doris
D
Taha
Pediatric Endocrinology, Trakya University, Faculty of Medicine, Edirne, Turkey.
Filiz
F
Tütüncüler
Department of Pediatrics, University Children's Medical Institute, National University Hospital, Singapore.
Goh Siok
GS
Ying
Department of Pediatrics, University Children's Medical Institute, National University Hospital, Singapore.
Loke Kah
LK
Yin
Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
Jining
J
Wang
Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
David
D
Feldman
D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D018389:Codon, Nonsense; D005091:Exons; D053098:Familial Hypophosphatemic Rickets / Q000235:genetics* / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense; D018167:Receptors, Calcitriol / Q000235:genetics*; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000378:metabolism
D018389:Codon, Nonsense; D018167:Receptors, Calcitriol; C579457:VDR protein, human; D014807:Vitamin D; C097949:1,25-dihydroxyvitamin D
HVDRR; Hypocalcemia; Mutations; Rickets; Vitamin D; Vitamin D receptor