DOI: 10.1359/jbmr.1999.14.5.730. Novel Mutations in the 1α-Hydroxylase (P450c1) Gene in Three Families with Pseudovitamin D–Deficiency Rickets Resulting in Loss of Functional Enzyme Activity in Blood-Derived Macrophages

Novel Mutations in the 1α-Hydroxylase (P450c1) Gene in Three Families with Pseudovitamin D–Deficiency Rickets Resulting in Loss of Functional Enzyme Activity in Blood-Derived Macrophages

10.1359/jbmr.1999.14.5.730

Crossref journal-article

Oxford University Press (OUP)

Journal of Bone and Mineral Research (286)

Abstract

Abstract 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-1α-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 γ–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.

Bibliography

Smith, S. J., Rucka, A. K., Berry, J. L., Davies, M., Mylchreest, S., Paterson, C. R., Heath, D. A., Tassabehji, M., Read, A. P., Mee, A. P., & Prof. Mawer, E. B. (1999). Novel Mutations in the 1Î±-Hydroxylase (P450c1) Gene in Three Families with Pseudovitamin DâDeficiency Rickets Resulting in Loss of Functional Enzyme Activity in Blood-Derived Macrophages. Journal of Bone and Mineral Research, 14(5), 730â739.

Authors 11

S. J. Smith (first)
A. K. Rucka (additional)
J. L. Berry (additional)
M. Davies (additional)
S. Mylchreest (additional)
C. R. Paterson (additional)
D. A. Heath (additional)
M. Tassabehji (additional)
A. P. Read (additional)
A. P. Mee (additional)
E. B. Prof. Mawer (additional)

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10.1111/j.1432-1033.1987.tb10915.x / Eur J Biochem / Kinetics and regulation of 25-hydroxycholecalciferol 1-alpha-hydroxylase from cells isolated from human term decidua by Delvin (1987)
{'key': '2024020713374514400_bib4', 'first-page': '1709S', 'article-title': '1,25(OH)2D3-regulated human keratinocyte proliferation and differentiation: Basic studies and their clinical application', 'volume': '125', 'author': 'Bikle', 'year': '1995', 'journal-title': 'J Nutr'} / J Nutr / 1,25(OH)2D3-regulated human keratinocyte proliferation and differentiation: Basic studies and their clinical application by Bikle (1995)
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Dates

Type	When
Created	19 years, 4 months ago (April 26, 2006, 4:14 p.m.)
Deposited	1 year, 5 months ago (March 13, 2024, 10:58 a.m.)
Indexed	3 months ago (June 3, 2025, 3:46 p.m.)
Issued	26 years, 4 months ago (May 1, 1999)
Published	26 years, 4 months ago (May 1, 1999)
Published Online	15 years, 9 months ago (Dec. 2, 2009)
Published Print	26 years, 4 months ago (May 1, 1999)

Funders 0

None

BibTeX

@article{Smith_1999, title={Novel Mutations in the 1α-Hydroxylase (P450c1) Gene in Three Families with Pseudovitamin D–Deficiency Rickets Resulting in Loss of Functional Enzyme Activity in Blood-Derived Macrophages}, volume={14}, ISSN={1523-4681}, url={http://dx.doi.org/10.1359/jbmr.1999.14.5.730}, DOI={10.1359/jbmr.1999.14.5.730}, number={5}, journal={Journal of Bone and Mineral Research}, publisher={Oxford University Press (OUP)}, author={Smith, S. J. and Rucka, A. K. and Berry, J. L. and Davies, M. and Mylchreest, S. and Paterson, C. R. and Heath, D. A. and Tassabehji, M. and Read, A. P. and Mee, A. P. and Prof. Mawer, E. B.}, year={1999}, month=may, pages={730–739} }

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  "abstract": "<jats:title>Abstract</jats:title>\n               <jats:p>Pseudovitamin D\u2013defiency 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-1\u03b1-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 \u03b3\u2013inducible 1-OHase activity in blood-derived macrophages was shown by 1,25(OH)2D synthesis in all control cells tested (37\u2013184 fmol/h/106 cells) and those from the PDDR family parents (34\u2013116 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.</jats:p>",
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