{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,4,6]],"date-time":"2025-04-06T01:28:18Z","timestamp":1743902898522},"reference-count":34,"publisher":"The Endocrine Society","issue":"11","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[1999,11,1]]},"abstract":"<jats:p>Pseudovitamin D deficiency rickets (PDDR) is an autosomal recessive disorder caused by defect in the activation of vitamin D. We recently isolated 25-hydroxyvitamin D3 1\u03b1-hydroxylase gene and identified four homozygous inactivating missense mutations in this gene by analysis of four typical cases of PDDR. This disease shows some phenotypic variation, and it has been suspected that patients with mild phenotypes have mutations that do not totally abolish the enzyme activity. To investigate the molecular defects associated with the phenotypic variation, we analyzed six additional unrelated PDDR patients: one with mild and five with typical clinical manifestation. By sequence analysis, all six patients were proven to have mutations in both alleles. The mutations varied, and we identified four novel missense mutations, a nonsense mutation, and a splicing mutation for the first time. The patient with mild clinical symptoms was compound heterozygous for T321R and a splicing mutation. The splice site mutation caused intron retention. Enzyme activity of the T321R mutant was analyzed by overexpressing the mutant 1\u03b1-hydroxylase in Escherichia coli cells to detect the subtle residual enzyme activity. No residual enzyme activity was detected in T321R mutant or in the other mutants. These results indicate that all of the patients, including those of mild phenotype, are caused by 1\u03b1-hydroxylase gene mutations that totally abolish the enzyme activity.<\/jats:p>","DOI":"10.1210\/jcem.84.11.6131","type":"journal-article","created":{"date-parts":[[2014,1,8]],"date-time":"2014-01-08T17:04:07Z","timestamp":1389200647000},"page":"4111-4117","source":"Crossref","is-referenced-by-count":4,"title":["No Enzyme Activity of 25-Hydroxyvitamin D3 1\u03b1-Hydroxylase Gene Product in Pseudovitamin D Deficiency Rickets, Including That with Mild Clinical Manifestation"],"prefix":"10.1210","volume":"84","author":[{"given":"Sachiko","family":"Kitanaka","sequence":"first","affiliation":[{"name":"Institute of Molecular and Cellular Biosciences (S.Ki., A.M., K.T., S.Ka.), 113-0032 Tokyo"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akiko","family":"Murayama","sequence":"additional","affiliation":[{"name":"Institute of Molecular and Cellular Biosciences (S.Ki., A.M., K.T., S.Ka.), 113-0032 Tokyo"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toshiyuki","family":"Sakaki","sequence":"additional","affiliation":[{"name":"Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University (T.S., K.I.), 606-8502 Kyoto"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kuniyo","family":"Inouye","sequence":"additional","affiliation":[{"name":"Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University (T.S., K.I.), 606-8502 Kyoto"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshiki","family":"Seino","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Okayama University Medical School (Y.S.), 700-0914 Okayama"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seiji","family":"Fukumoto","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine (S.F.), The University of Tokyo, 113-0032 Tokyo"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masaaki","family":"Shima","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Osaka University Medical School (M.S.), 565-0871 Osaka"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shigenori","family":"Yukizane","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Child Health, Kurume University Medical School (S.Y.), 830-0011 Fukuoka"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masaki","family":"Takayanagi","sequence":"additional","affiliation":[{"name":"Division of Metabolism, Chiba Children\u2019s Hospital (M.T.), 266-0007 Chiba"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroo","family":"Niimi","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Chiba University School of Medicine (H.N.), 260-8677 Chiba"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ken-ichi","family":"Takeyama","sequence":"additional","affiliation":[{"name":"Institute of Molecular and Cellular Biosciences (S.Ki., A.M., K.T., S.Ka.), 113-0032 Tokyo"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shigeaki","family":"Kato","sequence":"additional","affiliation":[{"name":"Institute of Molecular and Cellular Biosciences (S.Ki., A.M., K.T., S.Ka.), 113-0032 Tokyo"},{"name":"Core Research for Evolutional Science and Technology, Japan Science and Technology Corp. (S.Ka.), 332-0012 Saitama, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"80","reference":[{"key":"2020071622425484700_R1","first-page":"452","article-title":"Eine besondere Form des prima\u0308re vitamin-D-resistenten Rachitis mit Hypocalca\u0308mie und autosomal-dominanten Erbgang: die heredita\u0308re PseudoMangelrachitis.","volume":"16","author":"Prader","year":"1961","journal-title":"Helv Paediatr Acta"},{"key":"2020071622425484700_R2","author":"Balsan","year":"1991"},{"key":"2020071622425484700_R3","author":"Demay","year":"1995"},{"key":"2020071622425484700_R4","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1056\/NEJM197811022991803","article-title":"Serum 1,25-dihydroxyvitamin D levels in normal subjects and in patients with hereditary rickets or bone disease.","volume":"299","author":"Scriver","year":"1978","journal-title":"N Engl J Med"},{"key":"2020071622425484700_R5","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/S0022-3476(81)80952-3","article-title":"Vitamin D dependency: replacement therapy with calcitriol?","volume":"99","author":"Delvin","year":"1981","journal-title":"J Pediatr"},{"key":"2020071622425484700_R6","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1056\/NEJM197310182891601","article-title":"Pathogenesis of hereditary vitamin-D-dependent rickets. An inborn error of vitamin D metabolism involving defective conversion of 25-hydroxyvitamin D to 1\u03b1:25-dihydroxyvitamin D.","volume":"289","author":"Fraser","year":"1973","journal-title":"N Engl J Med"},{"key":"2020071622425484700_R7","doi-asserted-by":"crossref","first-page":"964","DOI":"10.1136\/adc.55.12.964","article-title":"Late presentation of vitamin D-dependent rickets.","volume":"55","author":"Cowen","year":"1980","journal-title":"Arch Dis Child"},{"key":"2020071622425484700_R8","doi-asserted-by":"crossref","first-page":"1827","DOI":"10.1126\/science.277.5333.1827","article-title":"25-Hydroxyvitamin D3 1\u03b1-hydroxylase and vitamin D synthesis.","volume":"277","author":"Takeyama","year":"1997","journal-title":"Science"},{"key":"2020071622425484700_R9","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1056\/NEJM199803053381004","article-title":"Inactivating mutations in the 25-hydroxyvitamin D3 1\u03b1-hydroxylase gene in patients with pseudovitamin D-deficiency rickets.","volume":"338","author":"Kitanaka","year":"1998","journal-title":"N Engl J Med"},{"key":"2020071622425484700_R10","first-page":"1961","article-title":"Cloning of human 25-hydroxyvitamin D-1\u03b1-hydroxylase and mutations causing vitamin D-dependent rickets type I.","volume":"11","author":"Fu","year":"1997","journal-title":"Mol Endocrinol"},{"key":"2020071622425484700_R11","doi-asserted-by":"crossref","first-page":"1499","DOI":"10.1089\/dna.1997.16.1499","article-title":"Complete structure of the human gene for the vitamin D 1\u03b1-hydroxylase, P450c1\u03b1.","volume":"16","author":"Fu","year":"1997","journal-title":"DNA Cell Biol"},{"key":"2020071622425484700_R12","doi-asserted-by":"crossref","first-page":"1694","DOI":"10.1086\/302156","article-title":"Genetics of vitamin D 1\u03b1-hydroxylase deficiency in 17 families.","volume":"63","author":"Wang","year":"1998","journal-title":"Am J Hum Genet"},{"key":"2020071622425484700_R13","doi-asserted-by":"crossref","first-page":"1437","DOI":"10.1046\/j.1523-1755.1998.00133.x","article-title":"Two novel 1\u03b1-hydroxylase mutations in French-Canadians with vitamin D dependency rickets type I.","volume":"54","author":"Yoshida","year":"1998","journal-title":"Kidney Int"},{"key":"2020071622425484700_R14","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1038\/ng0897-391","article-title":"Mice lacking the vitamin D receptor exhibit impaired bone formation, uterine hypoplasia and growth retardation after weaning.","volume":"16","author":"Yoshizawa","year":"1997","journal-title":"Nat Genet"},{"key":"2020071622425484700_R15","doi-asserted-by":"crossref","first-page":"2224","DOI":"10.1210\/endo.140.5.6691","article-title":"Positive and negative regulations of the renal 25-hydroxyvitamin D3 1\u03b1-hydroxylase gene by parathyroid hormone, calcitonin and 1\u03b1,25-(OH)2D3 in intact animals.","volume":"140","author":"Murayama","year":"1999","journal-title":"Endocrinology"},{"key":"2020071622425484700_R16","first-page":"117","article-title":"Clinical studies on vitamin D dependency: response to vitamin D.","volume":"27","author":"Shimotsuji","year":"1977","journal-title":"Med J Osaka Univ"},{"key":"2020071622425484700_R17","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1297\/cpe.1.83","article-title":"A case of vitamin D dependency type I.","volume":"1","author":"Matsumoto","year":"1992","journal-title":"Clin Pediatr Endocrinol"},{"key":"2020071622425484700_R18","first-page":"1765","article-title":"A case of vitamin D dependent rickets type 1, which has symptom free period for about 10 years.","volume":"41","author":"Sugawara","year":"1990","journal-title":"Seikeigeka"},{"key":"2020071622425484700_R19","first-page":"4054","article-title":"A new compound heterozygous mutation in the 11\u03b2-hydroxysteroid dehydrogenase type 2 gene in a case of apparent mineralocorticoid excess.","volume":"82","author":"Kitanaka","year":"1997","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071622425484700_R20","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1006\/bbrc.1998.9098","article-title":"The promoter of the human 25-hydroxyvitamin D3 1\u03b1-hydroxylase gene confers positive and negative responsiveness to PTH, calcitonin, and 1\u03b1,25-(OH)2D3.","volume":"249","author":"Murayama","year":"1998","journal-title":"Biochem Biophys Res Commun"},{"key":"2020071622425484700_R21","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1046\/j.1432-1327.1999.00096.x","article-title":"Enzymatic properties of mouse 25-hydroxyvitamin D3 1\u03b1-hydroxylase expressed in Escherichia coli.","volume":"259","author":"Sakaki","year":"1999","journal-title":"Eur J Biochem"},{"key":"2020071622425484700_R22","first-page":"259","volume":"2","author":"Cooper","year":"1995"},{"key":"2020071622425484700_R23","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1111\/j.1432-1033.1994.00335.x","article-title":"Further oxidation of hydroxycalcidiol by calcidiol 24-hydroxylase. A study with the mature enzyme expressed in Escherichia coli.","volume":"224","author":"Akiyoshi","year":"1994","journal-title":"Eur J Biochem"},{"key":"2020071622425484700_R24","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1006\/abbi.1997.0142","article-title":"Expression, purification, and enzymatic properties of recombinant human cytochrome P450c27 (CYP27).","volume":"343","author":"Pikuleva","year":"1997","journal-title":"Arch Biochem Biophys"},{"key":"2020071622425484700_R25","doi-asserted-by":"crossref","first-page":"7823","DOI":"10.1073\/pnas.86.20.7823","article-title":"Uncoupling of the cytochrome P-450cam monooxygenase reaction by a single mutation, threonine-252 to alanine or valine: possible role of the hydroxy amino acid in oxygen activation.","volume":"86","author":"Imai","year":"1989","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071622425484700_R26","first-page":"270","article-title":"Novel CYP11B1 mutations in congenital adrenal hyperplasia due to steroid 11\u03b2-hydroxylase deficiency.","volume":"83","author":"Merke","year":"1998","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071622425484700_R27","doi-asserted-by":"crossref","first-page":"10014","DOI":"10.1073\/pnas.91.21.10014","article-title":"Liver mitochondrial cytochrome P450 CYP27 and recombinant-expressed human CYP27 catalyze 1\u03b1-hydroxylation of 25-hydroxyvitamin D3.","volume":"91","author":"Axen","year":"1994","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071622425484700_R28","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1055\/s-2007-980002","article-title":"1,25-Dihydroxyvitamin D synthesis in rat liver microsomes.","volume":"27","author":"Negrea","year":"1995","journal-title":"Horm Metab Res"},{"key":"2020071622425484700_R29","first-page":"234","volume":"1407","author":"Axen","year":"1998"},{"key":"2020071622425484700_R30","doi-asserted-by":"crossref","first-page":"1240","DOI":"10.1093\/jn\/111.7.1240","article-title":"Vitamin D and its metabolites in human and bovine milk.","volume":"111","author":"Hollis","year":"1981","journal-title":"J Nutr"},{"key":"2020071622425484700_R31","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/0024-3205(91)90355-F","article-title":"The existence of 25-hydroxyvitamin D3\u20131\u03b1-hydroxylase in the liver of carp and bastard halibut.","volume":"48","author":"Takeuchi","year":"1991","journal-title":"Life Sci"},{"key":"2020071622425484700_R32","first-page":"421","article-title":"Disorders of steroid 11\u03b2-hydroxylase isozymes.","volume":"15","author":"White","year":"1994","journal-title":"Endocr Rev"},{"key":"2020071622425484700_R33","doi-asserted-by":"crossref","first-page":"4543","DOI":"10.1073\/pnas.90.10.4543","article-title":"Isolation and expression of human 1,25-dihydroxyvitamin D3 24-hydroxylase cDNA.","volume":"90","author":"Chen","year":"1993","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071622425484700_R34","doi-asserted-by":"crossref","first-page":"8668","DOI":"10.1073\/pnas.90.18.8668","article-title":"Transfected human liver cytochrome P-450 hydroxylates vitamin D analogs at different side-chain positions.","volume":"90","author":"Guo","year":"1993","journal-title":"Proc Natl Acad Sci USA"}],"container-title":["The Journal of Clinical Endocrinology &amp; Metabolism"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/jcem\/article-pdf\/84\/11\/4111\/9216597\/jcem4111.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/jcem\/article-pdf\/84\/11\/4111\/9216597\/jcem4111.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,7,17]],"date-time":"2020-07-17T11:13:18Z","timestamp":1594984398000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jcem\/article\/84\/11\/4111\/2864565"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1999,11,1]]},"references-count":34,"journal-issue":{"issue":"11","published-print":{"date-parts":[[1999,11,1]]}},"URL":"https:\/\/doi.org\/10.1210\/jcem.84.11.6131","relation":{},"ISSN":["0021-972X","1945-7197"],"issn-type":[{"value":"0021-972X","type":"print"},{"value":"1945-7197","type":"electronic"}],"subject":[],"published":{"date-parts":[[1999,11,1]]}}}