PMID- 10320521
OWN - NLM
STAT- MEDLINE
DCOM- 19990615
LR  - 20191210
IS  - 0884-0431 (Print)
IS  - 0884-0431 (Linking)
VI  - 14
IP  - 5
DP  - 1999 May
TI  - Novel mutations in the 1alpha-hydroxylase (P450c1) gene in three families with
      pseudovitamin D-deficiency rickets resulting in loss of functional enzyme
      activity in blood-derived macrophages.
PG  - 730-9
AB  - Pseudovitamin D-defiency rickets (PDDR) is an autosomal recessive disorder
      characterized by hypocalcemia, rickets (which are resistant to treatment with
      vitamin D), and low or undetectable serum levels of 1,25-dihydroxyvitamin D
      (1,25(OH)2D). The symptoms are corrected with 1,25(OH)2D treatment, and the
      disease is now believed to result from a defect in the cytochrome P450 component 
      (P450c1; CYP27B1) of the renal 25-hydroxyvitamin D-1alpha-hydroxylase (1-OHase). 
      We have studied genomic DNA from three families with PDDR and have identified the
      same homozygous mutation in the P450c1 gene in two of the index cases, causing a 
      frameshift in exon 8, resulting in a premature stop codon in the heme-binding
      domain. The two cases in the third kindred were compound heterozygotes with
      missense mutations in exons 6 and 9. We have also identified a C/T polymorphism
      in intron 6 of the P450c1 genomic DNA. Interferon gamma-inducible 1-OHase
      activity in blood-derived macrophages was shown by 1,25(OH)2D synthesis in all
      control cells tested (37-184 fmol/h/106 cells) and those from the PDDR family
      parents (34-116 fmol/h/106 cells) but was totally absent from the patients'
      cells, indicating a defect in their macrophage 1-OHase, similar to the presumed
      renal defect. The assumption of similarity between the renal and macrophage
      P450c1 was supported by our ability to clone a 514 bp sequence, including the
      heme-binding region of the macrophage P450c1 cDNA from controls, which was
      identical to that published for both the renal and keratinocyte P450c1 cDNAs.
FAU - Smith, S J
AU  - Smith SJ
AD  - University Department of Medicine, Manchester Royal Infirmary, Manchester, United
      Kingdom.
FAU - Rucka, A K
AU  - Rucka AK
FAU - Berry, J L
AU  - Berry JL
FAU - Davies, M
AU  - Davies M
FAU - Mylchreest, S
AU  - Mylchreest S
FAU - Paterson, C R
AU  - Paterson CR
FAU - Heath, D A
AU  - Heath DA
FAU - Tassabehji, M
AU  - Tassabehji M
FAU - Read, A P
AU  - Read AP
FAU - Mee, A P
AU  - Mee AP
FAU - Mawer, E B
AU  - Mawer EB
LA  - eng
GR  - Wellcome Trust/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Bone Miner Res
JT  - Journal of bone and mineral research : the official journal of the American
      Society for Bone and Mineral Research
JID - 8610640
RN  - 0 (Ferredoxins)
RN  - 40013-87-4 (24,25-Dihydroxyvitamin D 3)
RN  - 42VZT0U6YR (Heme)
RN  - 9007-49-2 (DNA)
RN  - 9035-51-2 (Cytochrome P-450 Enzyme System)
RN  - EC 1.14.- (Steroid Hydroxylases)
RN  - EC 1.14.15.15 (CYP27A1 protein, human)
RN  - EC 1.14.15.15 (Cholestanetriol 26-Monooxygenase)
RN  - EC 1.14.15.18 (25-Hydroxyvitamin D3 1-alpha-Hydroxylase)
SB  - IM
MH  - 24,25-Dihydroxyvitamin D 3/metabolism
MH  - 25-Hydroxyvitamin D3 1-alpha-Hydroxylase/genetics
MH  - Base Sequence
MH  - Cells, Cultured
MH  - Child
MH  - Child, Preschool
MH  - Cholestanetriol 26-Monooxygenase
MH  - *Chromosomes, Human, Pair 12
MH  - Cloning, Molecular
MH  - Cytochrome P-450 Enzyme System/*genetics
MH  - DNA/chemistry/metabolism
MH  - Female
MH  - Ferredoxins/metabolism
MH  - Heme/metabolism
MH  - Humans
MH  - Infant
MH  - Introns
MH  - Macrophages/*enzymology
MH  - Male
MH  - Molecular Sequence Data
MH  - *Mutation
MH  - Pedigree
MH  - Polymorphism, Genetic
MH  - Rickets/enzymology/*genetics
MH  - Steroid Hydroxylases/*genetics
EDAT- 1999/05/13 00:00
MHDA- 1999/05/13 00:01
CRDT- 1999/05/13 00:00
PHST- 1999/05/13 00:00 [pubmed]
PHST- 1999/05/13 00:01 [medline]
PHST- 1999/05/13 00:00 [entrez]
AID - 10.1359/jbmr.1999.14.5.730 [doi]
PST - ppublish
SO  - J Bone Miner Res. 1999 May;14(5):730-9. doi: 10.1359/jbmr.1999.14.5.730.