An ochre mutation in the vitamin D receptor gene causes hereditary 1,25-dihydroxyvitamin D sub 3 -resistant rickets in three families

Journal Article · Fri Dec 01 04:00:00 EST 1989 · Proceedings of the National Academy of Sciences of the United States of America; (USA)

DOI:https://doi.org/10.1073/pnas.86.24.9783· OSTI ID:6921261

Ritchie, H H; Hughes, M R; Thompson, E T; Pike, J W; O'Malley, B W ^[1]; Malloy, P J; Feldman, D ^[2]; Hochberg, Z ^[3]

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1. Baylor College of Medicine, Houston, TX (USA)
2. Stanford Univ. School of Medicine, CA (USA)
3. Rambam Medical Center, Haifa (Israel)

Hereditary 1,25-dihydroxyvitamin D{sub 3}-resistant rickets is a rare autosomal-recessive disease resulting from target-organ resistance to the action of the active hormonal form of vitamin D. Four affected children from three related families with the classical syndrome of hereditary 1,25-dihydroxyvitamin D{sub 3}-resistant rickets and the absence of detectable binding to the vitamin D receptor (VDR) in cultured fibroblasts or lymphoblasts were examined for genetic abnormalities in the VDR gene. Genomic DNA from Epstein-Barr virus-transformed lymphoblasts of eight family members was isolated and amplified by polymerase chain reaction techniques. Amplified fragments containing the eight structural exons encoding the VDR protein were sequenced. The DNA from all affected children exhibited a single C {yields} A base substitution within exon 7 at nucleotide 970. Although the affected children were all homozygotic for the mutation, the four parents tested all exhibited both wild-type and mutant alleles, indicating a heterozygous state. Recreated mutant receptor exhibited no specific 1,25-({sup 3}H)dihydroxyvitamin D{sub 3} binding and failed to activate a cotransfected VDR promoter-reporter gene construct. Thus these findings identify an ochre mutation in a human steroid hormone receptor in patients with hereditary 1,25-dihydroxyvitamin D{sub 3}-resistant rickets.

• OSTI ID: 6921261
• Journal Information: Proceedings of the National Academy of Sciences of the United States of America; (USA), Journal Name: Proceedings of the National Academy of Sciences of the United States of America; (USA) Vol. 86:24; ISSN 0027-8424; ISSN PNASA
• Country of Publication: United States
• Language: English

Related Subjects

550401* -- Genetics-- Tracer Techniques
59 BASIC BIOLOGICAL SCIENCES
ANIMAL CELLS
BIOLOGICAL MATERIALS
BLOOD
BLOOD CELLS
BODY FLUIDS
CHOLECALCIFEROL
CONNECTIVE TISSUE CELLS
DISEASES
ELECTROPHORESIS
GENE MUTATIONS
HEREDITARY DISEASES
HYDROGEN COMPOUNDS
ISOTOPE APPLICATIONS
LEUKOCYTES
LYMPHOCYTES
MATERIALS
MEMBRANE PROTEINS
MUTATIONS
NUCLEIC ACIDS
OLIGONUCLEOTIDES
ORGANIC COMPOUNDS
PATHOGENESIS
PATIENTS
PROTEINS
RADIORECEPTOR ASSAY
RECEPTORS
SOMATIC CELLS
TRACER TECHNIQUES
TRANSCRIPTION
TRITIUM COMPOUNDS
VITAMIN D
VITAMINS