Inactivating Mutations in the 25-Hydroxyvitamin D(Sub 3) 1(alpha)-Hydroxylase Gene in Patients with Pseudovitamin D-Deficiency Rickets

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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 D(3)) 1(alpha)-hydroxylase, the key enzyme for the synthesis of 1(alpha),25-dihydroxyvitamin D(3)).


We cloned human 25-hydroxyvitamin D(3)) 1(alpha)-hydroxylase complementary DNA (cDNA) using a mouse 1(alpha)-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(alpha)-hydroxylase gene in four unrelated patients with pseudovitamin D-deficiency rickets by DNA-sequence analysis. Both the normal and the mutant 1(alpha)-hydroxylase proteins were expressed in COS-1 cells and were assayed for 1(alpha)-hydroxylase activity.


The gene for 25-hydroxyvitamin D(3)) 1(alpha)-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(alpha)-hydroxylase protein revealed that all four mutations abolished 1(alpha)-hydroxylase activity.


Inactivating mutations in the 25-hydroxyvitamin D(3)) 1(alpha)-hydroxylase gene are a cause of pseudovitamin D-deficiency rickets. (N Engl J Med 1998;338:653-61.)

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