title: Cytochrome P450 oxidoreductase deficiency: identification and characterization of biallelic mutations and genotype-phenotype correlations in 35 Japanese patients.
abstract: BACKGROUND
  Cytochrome P450 oxidoreductase (POR) deficiency is a rare autosomal recessive disorder characterized by skeletal dysplasia, adrenal dysfunction, disorders of sex development (DSD), and maternal virilization during pregnancy. Although multiple studies have been performed for this condition, several matters remain to be clarified, including the presence of manifesting heterozygosity and the underlying factors for clinical variability.
  
  
  OBJECTIVE
  The objective of the study was to examine such unresolved matters by detailed molecular studies and genotype-phenotype correlations.
  
  
  METHODS
  Thirty-five Japanese patients with POR deficiency participated in the study.
  
  
  RESULTS
  Mutation analysis revealed homozygosity for R457H in cases 1-14 (group A), compound heterozygosity for R457H and one apparently null mutation in cases 15-28 (group B), and other combinations of mutations in cases 29-35 (group C). In particular, FISH and RT-PCR sequencing analyses revealed an intragenic microdeletion in one apparent R457H homozygote, transcription failure of apparently normal alleles in three R457H heterozygotes, and nonsense mediated mRNA decay in two frameshift mutation-positive cases examined. Genotype-phenotype correlations indicated that skeletal features were definitely more severe, and adrenal dysfunction, 46,XY DSD, and pubertal failure were somewhat more severe in group B than group A, whereas 46,XX DSD and maternal virilization during pregnancy were similar between two groups. Notable findings also included the contrast between infrequent occurrence of 46,XY DSD and invariable occurrence of 46,XX DSD and pubertal growth pattern in group A mimicking that of aromatase deficiency.
  
  
  CONCLUSIONS
  The results argue against the heterozygote manifestation and suggest that the residual POR activity reflected by the R457H dosage constitutes the underlying factor for clinical variability in some features but not other features, probably due to the simplicity and complexity of POR-dependent metabolic pathways relevant to each phenotype.
authors.affiliation: Research Institute, National Center for Child Health and Development, Tokyo 157-8535, Japan. mfukami@nch.go.jp
authors.forename: Maki
authors.initials: M
authors.lastname: Fukami
authors.forename: Gen
authors.initials: G
authors.lastname: Nishimura
authors.forename: Keiko
authors.initials: K
authors.lastname: Homma
authors.forename: Toshiro
authors.initials: T
authors.lastname: Nagai
authors.forename: Keiichi
authors.initials: K
authors.lastname: Hanaki
authors.forename: Ayumi
authors.initials: A
authors.lastname: Uematsu
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Ishii
authors.forename: Chikahiko
authors.initials: C
authors.lastname: Numakura
authors.forename: Hirotake
authors.initials: H
authors.lastname: Sawada
authors.forename: Mariko
authors.initials: M
authors.lastname: Nakacho
authors.forename: Takanori
authors.initials: T
authors.lastname: Kowase
authors.forename: Katsuaki
authors.initials: K
authors.lastname: Motomura
authors.forename: Hidenori
authors.initials: H
authors.lastname: Haruna
authors.forename: Mihoko
authors.initials: M
authors.lastname: Nakamura
authors.forename: Akira
authors.initials: A
authors.lastname: Ohishi
authors.forename: Masanori
authors.initials: M
authors.lastname: Adachi
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Tajima
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Hasegawa
authors.forename: Tomonobu
authors.initials: T
authors.lastname: Hasegawa
authors.forename: Reiko
authors.initials: R
authors.lastname: Horikawa
authors.forename: Kenji
authors.initials: K
authors.lastname: Fujieda
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Ogata
mesh_terms: D000293:Adolescent; D000305:Adrenal Cortex Hormones / Q000378:metabolism; D000483:Alleles; D001847:Bone Diseases / Q000201:enzymology / Q000235:genetics; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D003577:Cytochrome P-450 Enzyme System / Q000172:deficiency* / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D018628:Gene Dosage; D014644:Genetic Variation; D005838:Genotype; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D007564:Japan; D008297:Male; D009154:Mutation / Q000235:genetics; D010088:Oxidoreductases / Q000172:deficiency* / Q000235:genetics*; D010641:Phenotype; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012741:Sexual Maturation; D055815:Young Adult
chemical_list: D000305:Adrenal Cortex Hormones; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases