Cytochrome P450 oxidoreductase deficiency

Identification and characterization of biallelic mutations and genotype-phenotype correlations in 35 Japanese patients

Maki Fukami, Gen Nishimura, Keiko Homma, Toshiro Nagai, Keiichi Hanaki, Ayumi Uematsu, Tomohiro Ishii, Chikahiko Numakura, Hirotake Sawada, Mariko Nakacho, Takanori Kowase, Katsuaki Motomura, Hidenori Haruna, Mihoko Nakamura, Akira Ohishi, Masanori Adachi, Toshihiro Tajima, Yukihiro Hasegawa, Tomonobu Hasegawa, Reiko Horikawa & 2 others Kenji Fujieda, Tsutomu Ogata

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

Context: 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. Patients: 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.

Original languageEnglish
Pages (from-to)1723-1731
Number of pages9
JournalJournal of Clinical Endocrinology and Metabolism
Volume94
Issue number5
DOIs
Publication statusPublished - 2009 May

Fingerprint

Antley-Bixler Syndrome Phenotype
Genetic Association Studies
XX Disorders of Sex Development 46
XY Disorders of Sex Development 46
Cytochrome P-450 Enzyme System
Virilism
Oxidoreductases
Heterozygote
Mutation
Nonsense Mediated mRNA Decay
Mothers
Disorders of Sex Development
Pregnancy
Frameshift Mutation
Homozygote
Metabolic Networks and Pathways
Aromatase
Transcription
Alleles
Phenotype

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Endocrinology
  • Biochemistry, medical
  • Endocrinology, Diabetes and Metabolism
  • Medicine(all)

Cite this

Cytochrome P450 oxidoreductase deficiency : Identification and characterization of biallelic mutations and genotype-phenotype correlations in 35 Japanese patients. / Fukami, Maki; Nishimura, Gen; Homma, Keiko; Nagai, Toshiro; Hanaki, Keiichi; Uematsu, Ayumi; Ishii, Tomohiro; Numakura, Chikahiko; Sawada, Hirotake; Nakacho, Mariko; Kowase, Takanori; Motomura, Katsuaki; Haruna, Hidenori; Nakamura, Mihoko; Ohishi, Akira; Adachi, Masanori; Tajima, Toshihiro; Hasegawa, Yukihiro; Hasegawa, Tomonobu; Horikawa, Reiko; Fujieda, Kenji; Ogata, Tsutomu.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 94, No. 5, 05.2009, p. 1723-1731.

Research output: Contribution to journalArticle

Fukami, M, Nishimura, G, Homma, K, Nagai, T, Hanaki, K, Uematsu, A, Ishii, T, Numakura, C, Sawada, H, Nakacho, M, Kowase, T, Motomura, K, Haruna, H, Nakamura, M, Ohishi, A, Adachi, M, Tajima, T, Hasegawa, Y, Hasegawa, T, Horikawa, R, Fujieda, K & Ogata, T 2009, 'Cytochrome P450 oxidoreductase deficiency: Identification and characterization of biallelic mutations and genotype-phenotype correlations in 35 Japanese patients', Journal of Clinical Endocrinology and Metabolism, vol. 94, no. 5, pp. 1723-1731. https://doi.org/10.1210/jc.2008-2816
Fukami, Maki ; Nishimura, Gen ; Homma, Keiko ; Nagai, Toshiro ; Hanaki, Keiichi ; Uematsu, Ayumi ; Ishii, Tomohiro ; Numakura, Chikahiko ; Sawada, Hirotake ; Nakacho, Mariko ; Kowase, Takanori ; Motomura, Katsuaki ; Haruna, Hidenori ; Nakamura, Mihoko ; Ohishi, Akira ; Adachi, Masanori ; Tajima, Toshihiro ; Hasegawa, Yukihiro ; Hasegawa, Tomonobu ; Horikawa, Reiko ; Fujieda, Kenji ; Ogata, Tsutomu. / Cytochrome P450 oxidoreductase deficiency : Identification and characterization of biallelic mutations and genotype-phenotype correlations in 35 Japanese patients. In: Journal of Clinical Endocrinology and Metabolism. 2009 ; Vol. 94, No. 5. pp. 1723-1731.
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abstract = "Context: 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. Patients: 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.",
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T2 - Identification and characterization of biallelic mutations and genotype-phenotype correlations in 35 Japanese patients

AU - Fukami, Maki

AU - Nishimura, Gen

AU - Homma, Keiko

AU - Nagai, Toshiro

AU - Hanaki, Keiichi

AU - Uematsu, Ayumi

AU - Ishii, Tomohiro

AU - Numakura, Chikahiko

AU - Sawada, Hirotake

AU - Nakacho, Mariko

AU - Kowase, Takanori

AU - Motomura, Katsuaki

AU - Haruna, Hidenori

AU - Nakamura, Mihoko

AU - Ohishi, Akira

AU - Adachi, Masanori

AU - Tajima, Toshihiro

AU - Hasegawa, Yukihiro

AU - Hasegawa, Tomonobu

AU - Horikawa, Reiko

AU - Fujieda, Kenji

AU - Ogata, Tsutomu

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N2 - Context: 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. Patients: 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.

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