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Previous Volume 338:653-662 March 5, 1998 Number 10 Next

Inactivating Mutations in the 25-Hydroxyvitamin D3 1-Hydroxylase Gene in Patients with Pseudovitamin D–Deficiency Rickets

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ABSTRACT

Background Pseudovitamin D–deficiency rickets is characterized by the early onset of rickets with hypocalcemia and is thought to be caused by a deficit in renal 25-hydroxyvitamin D₃ 1-hydroxylase, the key enzyme for the synthesis of 1,25-dihydroxyvitamin D₃.

Methods We cloned human 25-hydroxyvitamin D₃ 1-hydroxylase complementary DNA (cDNA) using a mouse 1-hydroxylase cDNA fragment as a probe. Its genomic structure was determined, and its chromosomal location was mapped by fluorescence in situ hybridization. We then identified mutations in the 1-hydroxylase gene in four unrelated patients with pseudovitamin D–deficiency rickets by DNA-sequence analysis. Both the normal and the mutant 1-hydroxylase proteins were expressed in COS-1 cells and were assayed for 1-hydroxylase activity.

Results The gene for 25-hydroxyvitamin D₃ 1-hydroxylase was mapped to chromosome 12q13.3, which had previously been reported to be the locus for pseudovitamin D–deficiency rickets by linkage analysis. Four different homozygous missense mutations were detected in this gene in the four patients with pseudovitamin D–deficiency rickets. The unaffected parents and one sibling tested were heterozygous for the mutations. Functional analysis of the mutant 1-hydroxylase protein revealed that all four mutations abolished 1-hydroxylase activity.

Conclusions Inactivating mutations in the 25-hydroxyvitamin D₃ 1-hydroxylase gene are a cause of pseudovitamin D–deficiency rickets.

Source Information

From the Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo (S. Kitanaka, K.T., A.M., T.S., J.Y., S. Kato); Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Saitama (S. Kato); the Faculty of Bioresources, Mie University, Mie (K.O., M.N.); Tokyo Metropolitan Kiyose Children's Hospital, Tokyo (Y.H.); the Department of Pediatrics, Chiba University School of Medicine, Chiba (H.N.); and the Department of Endocrinology and Metabolism, National Children's Medical Research Center, Tokyo (T.T.) — all in Japan.

Address reprint requests to Dr. Kato at the Institute of Molecular and Cellular Biosciences, University of Tokyo, Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.

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