title: Novel cytochrome P4501B1 (CYP1B1) gene mutations in Japanese patients with primary congenital glaucoma.
abstract: OBJECTIVE
  To investigate CYP1B1 gene mutations in Japanese patients with primary congenital glaucoma (PCG).
  
  
  METHODS
  Sixty-five unrelated Japanese patients with PCG were screened by PCR-single-strand conformational polymorphism (SSCP) analysis followed by direct sequencing. No patients were offspring of consanguineous marriages, a common occurrence among patients in previous reports. PCG haplotypes were constructed with intragenic polymorphisms in affected individuals. Three-dimensional atomic structures of human CYP1B1 and four mutant CYP1B1 sequences representing missense mutations were assembled using homology modeling and were regularized by an energy-minimization procedure.
  
  
  RESULTS
  Eleven novel mutations, including seven definite and four probable mutations, were detected in 13 (20%) of the 65 unrelated patients. Of the seven definite mutations, three were predicted to truncate the CYP1B1 open reading frame. The other four were missense mutations (Asp192Val, Ala330Phe, Val364Met, and Arg444Gln), all located in conserved core structures determining proper folding and heme-binding ability of cytochrome P450 molecules. Molecular modeling demonstrated that two of four mutations in positions 330 and 364 were structurally neutral, but Arg444Gln caused significant structural change. Of the four probable mutations, three were missense (Val198Ile, Val320Leu, and Glu499Gly); the other was a base substitution in the noncoding region of exon 1.
  
  
  CONCLUSIONS
  The 11 varied CYP1B1 mutations found in 13 unrelated Japanese patients with sporadic occurrence of PCG represent an allelic heterogeneity and may be unique to a specific population.
authors.affiliation: Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan. mashima@med.keio.ac.jp
authors.forename: Y
authors.initials: Y
authors.lastname: Mashima
authors.forename: Y
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Y
authors.initials: Y
authors.lastname: Sergeev
authors.forename: Y
authors.initials: Y
authors.lastname: Ohtake
authors.forename: T
authors.initials: T
authors.lastname: Tanino
authors.forename: I
authors.initials: I
authors.lastname: Kimura
authors.forename: H
authors.initials: H
authors.lastname: Miyata
authors.forename: M
authors.initials: M
authors.lastname: Aihara
authors.forename: H
authors.initials: H
authors.lastname: Tanihara
authors.forename: M
authors.initials: M
authors.lastname: Inatani
authors.forename: N
authors.initials: N
authors.lastname: Azuma
authors.forename: T
authors.initials: T
authors.lastname: Iwata
authors.forename: M
authors.initials: M
authors.lastname: Araie
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D002675:Child, Preschool; D065633:Cytochrome P-450 CYP1B1; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005901:Glaucoma / Q000151:congenital* / Q000208:ethnology; D006239:Haplotypes; D006801:Humans; D007223:Infant; D007564:Japan / Q000453:epidemiology; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D018807:Polymorphism, Single-Stranded Conformational; D051381:Rats; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid
chemical_list: D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; C585498:Cyp1b1 protein, mouse; C585499:Cyp1b1 protein, rat; D065633:Cytochrome P-450 CYP1B1