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The 25‐Hydroxyvitamin D 1‐Alpha‐Hydroxylase Gene Maps to the Pseudovitamin D‐Deficiency Rickets (PDDR) Disease Locus
Author(s) -
StArnaud René,
Messerlian Serge,
Moir Janet M.,
Omdahl John L.,
Glorieux Francis H.
Publication year - 1997
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1359/jbmr.1997.12.10.1552
Subject(s) - biology , locus (genetics) , gene , cyp17a1 , complementary dna , rickets , microbiology and biotechnology , parathyroid hormone , vitamin d and neurology , genetics , clone (java method) , gene expression , endocrinology , medicine , calcium
Pseudovitamin D‐deficiency rickets (PDDR) is an autosomal recessive disorder that may be due to impaired activity of 25‐hydroxyvitamin D‐1α‐hydroxylase, a renal cytochrome P450 enzyme (P450 1α ) of the vitamin D pathway. The disease locus for PDDR has been mapped by linkage analysis to 12q13‐q14, but the molecular defect underlying the enzyme dysfunction has remained elusive due to the lack of sequence information for the P450 1α gene (hereafter referred to as 1α‐OHase). We have used a probe derived from the rat 25‐hydroxyvitamin D‐24‐hydroxylase (CYP24; 24‐OHase) sequence to identify and clone the 1α‐OHase cDNA. The full‐length 1α‐OHase clone of 2.4 kb codes for a protein of predicted Mr 55 kDa. Functional activity of the cloned sequence was assessed using transient transfection, and the production of authentic 1α,25‐dihydroxyvitamin D 3 [1α,25(OH) 2 D 3 ] was confirmed using high performance liquid chromatography fractionation and time‐of‐flight mass spectrometry. The expression of the gene was analyzed in vitamin D–replete animals; treatment with 1α,25(OH) 2 D 3 reduced 1α‐OHase transcript levels by 70%, while administration of parathyroid hormone led to a 2‐fold increase in the expression of the gene, thus confirming the hormonal regulation previously described using biochemical methods. The rat cDNA was used to obtain a human genomic clone. Interestingly, the human 1α‐OHase gene mapped to 12q13.1‐q13.3, providing strong evidence that a mutation in the 1α‐OHase gene is responsible for the PDDR phenotype. The availability of a cloned sequence for 1α‐OHase generates novel tools for the study of the molecular etiology of PDDR, and will allow the investigation of other disturbances of vitamin D metabolism.