Congenital adrenal hyperplasia caused by mutant P450 oxidoreductase and human androgen synthesis: analytical study

Arlt, Wiebke; Walker, Elizabeth A.; Draper, Norman R.; Ivison, Hannah E; Ride, J.P.; Hammer, Fabian; Chalder, S.; Borucka-Mankiewicz, Maria; Hauffa, Berthold P.; Małunowicz, E; Stewart, Paul M.; Shackleton, Cedric

doi:10.1016/s0140-6736(04)16503-3

Cited by 327 publications

(367 citation statements)

References 30 publications

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“…POR-inactivating mutations, including missense, frameshift and splice site mutations, are scattered throughout the gene with no apparent hot spots. 92,93 The most frequent mutation in Caucasians is p.A287P, 92 while p.R457H is the most frequent mutation in Japanese populations. 94,95 In one study of 30 patients with POR deficiency from 11 countries, 23 POR mutations including a deletion and a partial duplication were detected by MLPA, and only 22% of unrelated patients carried homozygous POR mutations.…”

Section: P450 Oxidoreductase Deficiencymentioning

confidence: 99%

Genetics of Congenital Adrenal Hyperplasia

Hannah‐Shmouni

Chen²,

Merke

2017

Endocrinology and Metabolism Clinics of North America

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Section: P450 Oxidoreductase Deficiencymentioning

confidence: 99%

Genetics of Congenital Adrenal Hyperplasia

Hannah‐Shmouni

Chen²,

Merke

2017

Endocrinology and Metabolism Clinics of North America

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“…It is a key electron donor enzyme providing electrons from NADPH to all microsomal P450 enzymes (CYP), including the key enzymes in glucocorticoid and sex steroid synthesis, CYP17A1, CYP21A2, and CYP19A1. POR deficiency thus results in congenital adrenal hyperplasia, which manifests as combined deficiencies of 17α-hydroxylase, 17,20-lyase, and 21-hydroxylase [4,8]. In this case, inadequate cortisol and DHEA-sulfate responses to ACTH stimulation, and increased baseline levels of 17-OHP and ACTH, indicated compensated adrenal insufficiency.…”

Section: Discussionmentioning

confidence: 93%

“…Moreover, mutations in the FGFR2 gene have not been found in ABS patients with genital ambiguity or abnormal steroid profiles [13]. In 2004, mutations in the cytochrome P450 oxidoreductase (POR) gene were identified as the cause of ABS with ambiguous genitalia and abnormal steroidogenesis, establishing this syndrome as a distinct genetic entity [4,8].…”

Section: Introductionmentioning

confidence: 99%

A case of Antley-Bixler syndrome caused by compound heterozygous mutations of the cytochrome P450 oxidoreductase gene

Cheon

Kim

et al. 2008

Eur J Pediatr

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Antley-Bixler syndrome (ABS) is a skeletal malformation syndrome primarily affecting the skull and limbs. Although causal mutations in the FGFR2 gene have been found in some patients, mutations in the electron donor enzyme P450 oxidoreductase gene (POR) have recently been found to cause ABS in other patients. In addition to skeletal malformations, POR deficiency also causes glucocorticoid deficiency and congenital adrenal hyperplasia with ambiguous genitalia in both sexes. Here, we report on a 7-month-old Korean girl with ABS and ambiguous genitalia who was confirmed by POR gene analysis. Our patient showed typical skeletal findings with brachycephaly, mid-face hypoplasia, and radiohumeral synostosis. She also had partial labial fusion and a single urogenital orifice, as well as increased 17α-hydroxyprogesterone levels, suggesting a 21-hydroxylase deficiency. Cortisol and DHEA-sulfate response to rapid adrenocorticotropic hormone (ACTH) stimulation was inadequate. Direct sequencing of the POR gene revealed compound heterozygous mutations (I444fsX449 and R457H). This is the first report of a Korean patient with ABS caused by POR gene mutations.

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“…Most CAH result from mutations in a single gene, which encodes a single steroidogenic enzyme. A new CAH variant due to mutations in the gene encoding the protein P450 oxidoreductase (POR), which is an electron donor to all the microsomal P450 enzymes type II, was first described in 2004 (1,2). P450 oxidoreductase deficiency (PORD) causes partial and combined impairment of the key enzymes involved in steroidogenesis: P450c17(17α-hydroxylase/17,20 lyase), P450c21 (21-hydroxylase) and P450aro (aromatase).…”

Section: Introductionmentioning

confidence: 99%

“…However, the 17,20-lyase activity is often impaired, which compromises the synthesis of fetal androgenic precursors by the classical pathway. Consequently, the most accepted hypothesis is the androgen production by an alternative pathway during fetal life, called the "backdoor pathway", in which enzymes, such as SRD5A1 and AKR1C, convert 17OH-progesterone to dihydrotestosterone (DHT) (2,6,9).…”

Section: Introductionmentioning

confidence: 99%

Long-term follow-up of a female with congenital adrenal hyperplasia due to P450-oxidoreductase deficiency

Bonamichi

Santiago

Bertola

et al. 2016

Arch. Endocrinol. Metab.

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SUMMARYP450 oxidoreductase deficiency (PORD) is a variant of congenital adrenal hyperplasia that is caused by POR gene mutations. The POR gene encodes a flavor protein that transfers electrons from nicotinamide adenine dinucleotide phosphate (NADPH) to all microsomal cytochrome P450 type II (including 21-hydroxylase, 17α-hydroxylase 17,20 lyase and aromatase), which is fundamental for their enzymatic activity. POR mutations cause variable impairments in steroidogenic enzyme activities that result in wide phenotypic variability ranging from 46,XX or 46,XY disorders of sexual differentiation, glucocorticoid deficiency, with or without skeletal malformations similar to Antley-Bixler syndrome to asymptomatic newborns diagnosed during neonatal screening test. Little is known about the PORD long-term evolution. We described a 46,XX patient with mild atypical genitalia associated with severe bone malformation, who was diagnosed after 13 years due to sexual infantilism. She developed large ovarian cysts and late onset adrenal insufficiency during follow-up, both of each regressed after hormone replacement therapies. We also described a late surgical approach for the correction of facial hypoplasia in a POR patient. Arch Endocrinol Metab. 2016;60(5):500-4

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Congenital adrenal hyperplasia caused by mutant P450 oxidoreductase and human androgen synthesis: analytical study

Cited by 327 publications

References 30 publications

Genetics of Congenital Adrenal Hyperplasia

Genetics of Congenital Adrenal Hyperplasia

A case of Antley-Bixler syndrome caused by compound heterozygous mutations of the cytochrome P450 oxidoreductase gene

Long-term follow-up of a female with congenital adrenal hyperplasia due to P450-oxidoreductase deficiency

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