A new point mutation in the deoxyribonuclic acid-binding domain of the vitamine D receptor in a kindred with hereditary 1,25-dihydroxyvitamin d-resistant rickets

Journal Article · Mon Feb 01 04:00:00 EST 1993 · Journal of Clinical Endocrinology and Metabolism; (United States)

DOI:https://doi.org/10.1210/jc.76.2.509· OSTI ID:6827910

Yagi, Hideki; Miyake, Hiroshi; Nagashima, Kanji; Kuroume, Takayoshi ^[1]; Ozone, K; Pike, J W ^[2]

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1. Gunma Univ. School of Medicine (Japan)
2. Baylor College of Medicine, Houston, TX (United States)

Hereditary 1,25-dihydroxyvitamin D [1,25-(OH)[sub 2]D]-resistant rickets (HVDRR) is a rare disorder characterized by rickets, alopecia, hypocalcemia, secondary hyperparathyroidism, and normal or elevated serum 1,25-dihydroxyvitamin D levels. The authors describe a patient with typical clinical characteristics of HVDRR, except that elevated levels of serum phosphorus were present coincident with increased levels of serum intact PTH. The patient was treated with high dose calcium infusion after an ineffective treatment with 1[alpha]-hydroxyvitamin D[sub 3]; serum calcium and phosphorus as well as intact PTH and alkaline phosphatase levels were normalized. Evaluation of phytohemagglutinin-activated lymphocytes derived from this patient revealed that 1,25-(OH)[sub 2]D[sub 3] was unable to inhibit thymidine incooperation, a result that contrast with the capacity of 1,25-(OH)[sub 2]D[sub 3] to inhibit uptake into normal activated lymphocytes. 1,25-(OH)[sub 2]D[sub 3] did not induce human osteocalcin promoter activity after transfection of this DNA linked to a reporter gene into patient cells. Cointroduction of a human vitamin D receptor (VDR) cDNA expression vector with the reporter plasmid, however, restored the hormone response. Evaluation of extracts from the patient cells for VDR DNA binding revealed a defect in DNA binding. Analysis of genomic DNA from the patient's cells by PCR confirmed the presence of a point mutation in exon 2 of the VDR. This exon directs synthesis of a portion of the DNA-binding domain of the receptor. We conclude that the genetic basis for 1,25-(OH)[sub 2]D[sub 3] resistance in this kindred with VDR-positive HVDRR is due to a single base mutation in the VDR that leads to production of a receptor unable to interact appropriately with DNA. 20 refs., 3 figs., 1 tab.

• OSTI ID: 6827910
• Journal Information: Journal of Clinical Endocrinology and Metabolism; (United States), Journal Name: Journal of Clinical Endocrinology and Metabolism; (United States) Vol. 76:2; ISSN JCEMAZ; ISSN 0021-972X
• Country of Publication: United States
• Language: English

Related Subjects

550200 -- Biochemistry
550400* -- Genetics
59 BASIC BIOLOGICAL SCIENCES
ALKALINE EARTH METALS
CALCIUM
CHEMICAL BONDS
CLONING
DISEASES
DNA
DNA HYBRIDIZATION
DNA-CLONING
ELEMENTS
GENE MUTATIONS
HYBRIDIZATION
MEMBRANE PROTEINS
METABOLIC DISEASES
METALS
MUTATIONS
NUCLEIC ACIDS
ORGANIC COMPOUNDS
PROTEINS
RECEPTORS
RICKETS
SKELETAL DISEASES
VITAMIN D
VITAMINS