title: Two novel 1alpha-hydroxylase mutations in French-Canadians with vitamin D dependency rickets type I1.
abstract: BACKGROUND
  Vitamin D dependency rickets type I (VDDR-I) is an autosomal recessive disorder in which 25-hydroxyvitamin D 1alpha-hydroxylase (1alpha-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 1alpha-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 1alpha-hydroxylase mutations in French-Canadian patients with VDDR-I.
  
  
  METHODS
  The nine exons of the 1alpha-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.
  
  
  CONCLUSIONS
  We describe two novel 1alpha-hydroxylase mutations that are consistent with loss of function in four French-Canadian patients with VDDR-I and suggest that the 1alpha-hydroxylase mutations arise from more than one founder in this population.
authors.affiliation: Department of Internal Medicine, School of Medicine, Keio University, Shinjuku, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Yoshida
authors.forename: T
authors.initials: T
authors.lastname: Monkawa
authors.forename: H S
authors.initials: HS
authors.lastname: Tenenhouse
authors.forename: P
authors.initials: P
authors.lastname: Goodyer
authors.forename: T
authors.initials: T
authors.lastname: Shinki
authors.forename: T
authors.initials: T
authors.lastname: Suda
authors.forename: S
authors.initials: S
authors.lastname: Wakino
authors.forename: M
authors.initials: M
authors.lastname: Hayashi
authors.forename: T
authors.initials: T
authors.lastname: Saruta
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000235:genetics*; D002874:Chromosome Mapping; D006801:Humans; D009154:Mutation; D012150:Polymorphism, Restriction Fragment Length; D012279:Rickets / Q000235:genetics*
chemical_list: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase