Two novel 1α-hydroxylase mutations in French-Canadians with vitamin D dependency rickets type I

Tadashi Yoshida, Toshiaki Monkawa, Harriet S. Tenenhouse, Paul Goodyer, Toshimasa Shinki, Tatsuo Suda, Shu Wakino, Matsuhiko Hayashi, Takao Saruta

Research output: Contribution to journalArticle

69 Citations (Scopus)

Abstract

Background. Vitamin D dependency rickets type I (VDDR-I) is an autosomal recessive disorder in which 25-hydroxyvitamin D 1α-hydroxylase (1α- hydroxylase) activity in renal proximal tubules is deficient. VDDR-I is recognized throughout the world, but occurs more frequently in a subset of the French-Canadian population. We and others have recently cloned the human 1α-hydroxylase cDNA and gene, making it possible to screen for mutations. The first VDDR-I mutations were reported in one American and four Japanese patients. In this study, we screened for 1α-hydroxylase mutations in French- Canadian patients with VDDR-I. Methods. The nine exons of the 1α-hydroxylase gene were amplified by polymerase chain reaction (PCR) from genomic DNA of four unrelated French-Canadian patients with VDDR-I and their parents, and sequenced. Results. Three of the patients were homozygous for a single base- pair deletion (G) at position 262 in the cDNA that lies in exon 2, and causes a premature termination codon upstream from the putative ferredoxin- and heme-binding domains. The fourth patient was homozygous for a 7-bp insertion (CCCCCCA) at position 1323 of the cDNA that lies in exon 8, and causes a premature termination upstream from the putative heme-binding domain. In each family, obligate carriers have one copy of the mutant allele. These mutations, which could be detected by PCR-restriction fragment length polymorphism and polyacrylamide gel electrophoresis of the PCR products, were not found in 25 normal French-Canadians. Conclusion. We describe two novel lα-hydroxylase mutations that are consistent with loss of function in four French-Canadian patients with VDDR-I and suggest that the 1α-hydroxylase mutations arise from more than one founder in this population.

Original languageEnglish
Pages (from-to)1437-1443
Number of pages7
JournalKidney International
Volume54
Issue number5
DOIs
Publication statusPublished - 1998

Fingerprint

Rickets
Mixed Function Oxygenases
Vitamin D
Mutation
Exons
Complementary DNA
Heme
Polymerase Chain Reaction
Ferredoxins
Proximal Kidney Tubule
Nonsense Codon
Base Pairing
Restriction Fragment Length Polymorphisms
Population
Genes
Dependency (Psychology)
Polyacrylamide Gel Electrophoresis
Parents
Alleles
DNA

Keywords

  • 25-hydroxycholecalciferol-1-hydroxylase
  • Cytochrome P450
  • Gene mutation
  • Hypocalcemia
  • Mendelian disorder
  • Proximal tubules
  • Rachitic lesions
  • Vitamin D

ASJC Scopus subject areas

  • Nephrology

Cite this

Two novel 1α-hydroxylase mutations in French-Canadians with vitamin D dependency rickets type I. / Yoshida, Tadashi; Monkawa, Toshiaki; Tenenhouse, Harriet S.; Goodyer, Paul; Shinki, Toshimasa; Suda, Tatsuo; Wakino, Shu; Hayashi, Matsuhiko; Saruta, Takao.

In: Kidney International, Vol. 54, No. 5, 1998, p. 1437-1443.

Research output: Contribution to journalArticle

Yoshida, Tadashi ; Monkawa, Toshiaki ; Tenenhouse, Harriet S. ; Goodyer, Paul ; Shinki, Toshimasa ; Suda, Tatsuo ; Wakino, Shu ; Hayashi, Matsuhiko ; Saruta, Takao. / Two novel 1α-hydroxylase mutations in French-Canadians with vitamin D dependency rickets type I. In: Kidney International. 1998 ; Vol. 54, No. 5. pp. 1437-1443.
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abstract = "Background. Vitamin D dependency rickets type I (VDDR-I) is an autosomal recessive disorder in which 25-hydroxyvitamin D 1α-hydroxylase (1α- hydroxylase) activity in renal proximal tubules is deficient. VDDR-I is recognized throughout the world, but occurs more frequently in a subset of the French-Canadian population. We and others have recently cloned the human 1α-hydroxylase cDNA and gene, making it possible to screen for mutations. The first VDDR-I mutations were reported in one American and four Japanese patients. In this study, we screened for 1α-hydroxylase mutations in French- Canadian patients with VDDR-I. Methods. The nine exons of the 1α-hydroxylase gene were amplified by polymerase chain reaction (PCR) from genomic DNA of four unrelated French-Canadian patients with VDDR-I and their parents, and sequenced. Results. Three of the patients were homozygous for a single base- pair deletion (G) at position 262 in the cDNA that lies in exon 2, and causes a premature termination codon upstream from the putative ferredoxin- and heme-binding domains. The fourth patient was homozygous for a 7-bp insertion (CCCCCCA) at position 1323 of the cDNA that lies in exon 8, and causes a premature termination upstream from the putative heme-binding domain. In each family, obligate carriers have one copy of the mutant allele. These mutations, which could be detected by PCR-restriction fragment length polymorphism and polyacrylamide gel electrophoresis of the PCR products, were not found in 25 normal French-Canadians. Conclusion. We describe two novel lα-hydroxylase mutations that are consistent with loss of function in four French-Canadian patients with VDDR-I and suggest that the 1α-hydroxylase mutations arise from more than one founder in this population.",
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AU - Yoshida, Tadashi

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AU - Goodyer, Paul

AU - Shinki, Toshimasa

AU - Suda, Tatsuo

AU - Wakino, Shu

AU - Hayashi, Matsuhiko

AU - Saruta, Takao

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AB - Background. Vitamin D dependency rickets type I (VDDR-I) is an autosomal recessive disorder in which 25-hydroxyvitamin D 1α-hydroxylase (1α- hydroxylase) activity in renal proximal tubules is deficient. VDDR-I is recognized throughout the world, but occurs more frequently in a subset of the French-Canadian population. We and others have recently cloned the human 1α-hydroxylase cDNA and gene, making it possible to screen for mutations. The first VDDR-I mutations were reported in one American and four Japanese patients. In this study, we screened for 1α-hydroxylase mutations in French- Canadian patients with VDDR-I. Methods. The nine exons of the 1α-hydroxylase gene were amplified by polymerase chain reaction (PCR) from genomic DNA of four unrelated French-Canadian patients with VDDR-I and their parents, and sequenced. Results. Three of the patients were homozygous for a single base- pair deletion (G) at position 262 in the cDNA that lies in exon 2, and causes a premature termination codon upstream from the putative ferredoxin- and heme-binding domains. The fourth patient was homozygous for a 7-bp insertion (CCCCCCA) at position 1323 of the cDNA that lies in exon 8, and causes a premature termination upstream from the putative heme-binding domain. In each family, obligate carriers have one copy of the mutant allele. These mutations, which could be detected by PCR-restriction fragment length polymorphism and polyacrylamide gel electrophoresis of the PCR products, were not found in 25 normal French-Canadians. Conclusion. We describe two novel lα-hydroxylase mutations that are consistent with loss of function in four French-Canadian patients with VDDR-I and suggest that the 1α-hydroxylase mutations arise from more than one founder in this population.

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