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

S Kitanaka, K Takeyama, A Murayama… - … England Journal of …, 1998 - Mass Medical Soc
S Kitanaka, K Takeyama, A Murayama, T Sato, K Okumura, M Nogami, Y Hasegawa, H Niimi…
New England Journal of Medicine, 1998Mass Medical Soc
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 1α-hydroxylase, the key enzyme for the synthesis of 1α, 25-dihydroxyvitamin D3.
Methods We cloned human 25-hydroxyvitamin D3 1α-hydroxylase complementary DNA
(cDNA) using a mouse 1α-hydroxylase cDNA fragment as a probe. Its genomic structure was
determined, and its chromosomal location was mapped by fluorescence in situ hybridization …
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 1α-hydroxylase, the key enzyme for the synthesis of 1α,25-dihydroxyvitamin D3.
Methods
We cloned human 25-hydroxyvitamin D3 1α-hydroxylase complementary DNA (cDNA) using a mouse 1α-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 1α-hydroxylase gene in four unrelated patients with pseudovitamin D–deficiency rickets by DNA-sequence analysis. Both the normal and the mutant 1α-hydroxylase proteins were expressed in COS-1 cells and were assayed for 1α-hydroxylase activity.
Results
The gene for 25-hydroxyvitamin D3 1α-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 1α-hydroxylase protein revealed that all four mutations abolished 1α-hydroxylase activity.
Conclusions
Inactivating mutations in the 25-hydroxyvitamin D3 1α-hydroxylase gene are a cause of pseudovitamin D–deficiency rickets.
The New England Journal Of Medicine