Cytochrome P450 oxidoreductase gene mutations and antley-bixler syndrome with abnormal genitalia and/or impaired steroidogenesis

Molecular and clinical studies in 10 patients

Maki Fukami, Reiko Horikawa, Toshiro Nagai, Toshiaki Tanaka, Yasuhiro Naiki, Naoko Sato, Torayuki Okuyama, Hideo Nakai, Shun Soneda, Katsuhiko Tachibana, Nobutake Matsuo, Seiji Sato, Keiko Homma, Gen Nishimura, Tomonobu Hasegawa, Tsutomu Ogata

Research output: Contribution to journalArticle

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Abstract

We report on molecular and clinical findings in 10 Japanese patients (four males and six females) from eight families (two pairs of siblings and six isolated cases) with Antley-Bixler syndrome accompanied by abnormal genitalia and/or impaired steroidogenesis. Direct sequencing was performed for all the 15 exons of cytochrome P450 oxidoreductase gene (POR), showing two missense mutations (R457H and Y578C), a 24-bp deletion mutation resulting in loss of nine amino acids and creation of one amino acid (L612_W620delinsR), a single bp insertion mutation leading to frameshift (I444fsX449), and a silent mutation (G5G). R457H has previously been shown to be a pathologic mutation, and computerized modeling analyses indicated that the 15A>G for G5G could disturb an exonic splicing enhancer motif, and the remaining three mutations should affect protein conformations. Six patients were compound heterozygotes, and three patients were R457H homozygotes; no mutation was identified on one allele of the remaining one patient. Clinical findings included various degrees of skeletal features, such as brachycephaly, radiohumeral synostosis, and digital joint contractures in patients of both sexes, normal-to-poor masculinization during fetal and pubertal periods in male patients, virilization during fetal life and poor pubertal development without worsening of virilization in female patients, and relatively large height gain and delayed bone age from the pubertal period in patients of both sexes, together with maternal virilization during pregnancy. Blood cholesterol was grossly normal, and endocrine studies revealed defective CYP17A1 and CYP21A2 activities. The results suggest that Antley-Bixler syndrome with abnormal genitalia and/or impaired steroidogenesis is caused by POR mutations, and that clinical features are variable and primarily explained by impaired activities of POR-dependent CYP51A1, CYP17A1, CYP21A2, and CYP19A1.

Original languageEnglish
Pages (from-to)414-426
Number of pages13
JournalJournal of Clinical Endocrinology and Metabolism
Volume90
Issue number1
DOIs
Publication statusPublished - 2005 Jan

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Antley-Bixler Syndrome Phenotype
Genitalia
Cytochrome P-450 Enzyme System
Oxidoreductases
Genes
Mutation
Virilism
Amino Acids
Conformations
Exons
Bone
Blood
Cholesterol
Synostosis
Craniosynostoses
Protein Conformation
Clinical Studies
Sequence Deletion
Insertional Mutagenesis
Homozygote

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology, Diabetes and Metabolism

Cite this

Cytochrome P450 oxidoreductase gene mutations and antley-bixler syndrome with abnormal genitalia and/or impaired steroidogenesis : Molecular and clinical studies in 10 patients. / Fukami, Maki; Horikawa, Reiko; Nagai, Toshiro; Tanaka, Toshiaki; Naiki, Yasuhiro; Sato, Naoko; Okuyama, Torayuki; Nakai, Hideo; Soneda, Shun; Tachibana, Katsuhiko; Matsuo, Nobutake; Sato, Seiji; Homma, Keiko; Nishimura, Gen; Hasegawa, Tomonobu; Ogata, Tsutomu.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 90, No. 1, 01.2005, p. 414-426.

Research output: Contribution to journalArticle

Fukami, M, Horikawa, R, Nagai, T, Tanaka, T, Naiki, Y, Sato, N, Okuyama, T, Nakai, H, Soneda, S, Tachibana, K, Matsuo, N, Sato, S, Homma, K, Nishimura, G, Hasegawa, T & Ogata, T 2005, 'Cytochrome P450 oxidoreductase gene mutations and antley-bixler syndrome with abnormal genitalia and/or impaired steroidogenesis: Molecular and clinical studies in 10 patients', Journal of Clinical Endocrinology and Metabolism, vol. 90, no. 1, pp. 414-426. https://doi.org/10.1210/jc.2004-0810
Fukami, Maki ; Horikawa, Reiko ; Nagai, Toshiro ; Tanaka, Toshiaki ; Naiki, Yasuhiro ; Sato, Naoko ; Okuyama, Torayuki ; Nakai, Hideo ; Soneda, Shun ; Tachibana, Katsuhiko ; Matsuo, Nobutake ; Sato, Seiji ; Homma, Keiko ; Nishimura, Gen ; Hasegawa, Tomonobu ; Ogata, Tsutomu. / Cytochrome P450 oxidoreductase gene mutations and antley-bixler syndrome with abnormal genitalia and/or impaired steroidogenesis : Molecular and clinical studies in 10 patients. In: Journal of Clinical Endocrinology and Metabolism. 2005 ; Vol. 90, No. 1. pp. 414-426.
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AU - Horikawa, Reiko

AU - Nagai, Toshiro

AU - Tanaka, Toshiaki

AU - Naiki, Yasuhiro

AU - Sato, Naoko

AU - Okuyama, Torayuki

AU - Nakai, Hideo

AU - Soneda, Shun

AU - Tachibana, Katsuhiko

AU - Matsuo, Nobutake

AU - Sato, Seiji

AU - Homma, Keiko

AU - Nishimura, Gen

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