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

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Title: Congenital adrenal hyperplasia caused by mutant P450 oxidoreductase and human androgen synthesis: analytical study.
Authors: Arlt, Wiebke, Walker, Elizabeth A., Draper, Nicole, Ivison, Hannah E., Ride, Jon P., Hammer, Fabian, Chalder, Susan M., Borucka-Mankiewicz, Maria, Hauffa, Berthold P., Malunowicz, Ewa M., Stewart, Paul M., Shackleton, Cedric H. L.
Source: Lancet. 6/26/2004, Vol. 363 Issue 9427, p2128-2135. 8p. 3 Color Photographs, 3 Diagrams, 3 Charts.
Subjects: Androgens, Hyperplasia, Genetic mutation, Enzymes, Biomolecules, Proteins, Chemical ecology, Genes, Sex hormones, Cytochromes, Genetic disorders, Genetics
Abstract: Background: Congenital adrenal hyperplasia with apparent combined P450C17 and P450C21 deficiency is associated with accumulation of steroid metabolites, indicating impaired activity of 17alpha-hydroxylase and 21-hydroxylase. However, no mutations have been reported in the CYP17 and CYP21 genes, which encode these P450 enzymes. Affected girls are born with ambiguous genitalia, but their circulating androgens are low, and virilisation does not progress. We aimed to investigate the underlying molecular basis of congenital adrenal hyperplasia with apparent combined P450C17 and P450C21 deficiency in affected children.Methods: We did sequence analysis of the human gene encoding P450 oxidoreductase, an enzyme that is important in electron transfer from NADPH to P450C17 and P450C21. We studied two unrelated families with a total of three affected children and 100 healthy controls. Wild-type and mutant P450 oxidoreductase proteins were bacterially expressed, purified, and assayed for cytochrome c reductase activity.Findings: We identified four mutations encoding single aminoacid changes in P450 oxidoreductase. All patients were compound heterozygotes, whereas their parents and an unaffected sibling harboured a mutation in only one allele. By contrast, no mutations were noted in the controls. Bacterial expression of recombinant mutant proteins revealed deficient or reduced enzyme activity.Interpretation: Molecular pathogenesis of this form of congenital adrenal hyperplasia is caused by mutations in the gene encoding P450 oxidoreductase. Deficiency of this enzyme could suggest an alternative pathway in human androgen synthesis, present only in fetal life, which explains the combination of antenatal androgen excess and postnatal androgen deficiency. [ABSTRACT FROM AUTHOR]
Copyright of Lancet is the property of Lancet and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Psychology and Behavioral Sciences Collection
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  Data: Congenital adrenal hyperplasia caused by mutant P450 oxidoreductase and human androgen synthesis: analytical study.
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  Data: <searchLink fieldCode="AR" term="%22Arlt%2C+Wiebke%22">Arlt, Wiebke</searchLink><br /><searchLink fieldCode="AR" term="%22Walker%2C+Elizabeth+A%2E%22">Walker, Elizabeth A.</searchLink><br /><searchLink fieldCode="AR" term="%22Draper%2C+Nicole%22">Draper, Nicole</searchLink><br /><searchLink fieldCode="AR" term="%22Ivison%2C+Hannah+E%2E%22">Ivison, Hannah E.</searchLink><br /><searchLink fieldCode="AR" term="%22Ride%2C+Jon+P%2E%22">Ride, Jon P.</searchLink><br /><searchLink fieldCode="AR" term="%22Hammer%2C+Fabian%22">Hammer, Fabian</searchLink><br /><searchLink fieldCode="AR" term="%22Chalder%2C+Susan+M%2E%22">Chalder, Susan M.</searchLink><br /><searchLink fieldCode="AR" term="%22Borucka-Mankiewicz%2C+Maria%22">Borucka-Mankiewicz, Maria</searchLink><br /><searchLink fieldCode="AR" term="%22Hauffa%2C+Berthold+P%2E%22">Hauffa, Berthold P.</searchLink><br /><searchLink fieldCode="AR" term="%22Malunowicz%2C+Ewa+M%2E%22">Malunowicz, Ewa M.</searchLink><br /><searchLink fieldCode="AR" term="%22Stewart%2C+Paul+M%2E%22">Stewart, Paul M.</searchLink><br /><searchLink fieldCode="AR" term="%22Shackleton%2C+Cedric+H%2E+L%2E%22">Shackleton, Cedric H. L.</searchLink>
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  Data: <searchLink fieldCode="JN" term="%22Lancet%22">Lancet</searchLink>. 6/26/2004, Vol. 363 Issue 9427, p2128-2135. 8p. 3 Color Photographs, 3 Diagrams, 3 Charts.
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  Data: <searchLink fieldCode="DE" term="%22Androgens%22">Androgens</searchLink><br /><searchLink fieldCode="DE" term="%22Hyperplasia%22">Hyperplasia</searchLink><br /><searchLink fieldCode="DE" term="%22Genetic+mutation%22">Genetic mutation</searchLink><br /><searchLink fieldCode="DE" term="%22Enzymes%22">Enzymes</searchLink><br /><searchLink fieldCode="DE" term="%22Biomolecules%22">Biomolecules</searchLink><br /><searchLink fieldCode="DE" term="%22Proteins%22">Proteins</searchLink><br /><searchLink fieldCode="DE" term="%22Chemical+ecology%22">Chemical ecology</searchLink><br /><searchLink fieldCode="DE" term="%22Genes%22">Genes</searchLink><br /><searchLink fieldCode="DE" term="%22Sex+hormones%22">Sex hormones</searchLink><br /><searchLink fieldCode="DE" term="%22Cytochromes%22">Cytochromes</searchLink><br /><searchLink fieldCode="DE" term="%22Genetic+disorders%22">Genetic disorders</searchLink><br /><searchLink fieldCode="DE" term="%22Genetics%22">Genetics</searchLink>
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  Data: <bold>Background: </bold>Congenital adrenal hyperplasia with apparent combined P450C17 and P450C21 deficiency is associated with accumulation of steroid metabolites, indicating impaired activity of 17alpha-hydroxylase and 21-hydroxylase. However, no mutations have been reported in the CYP17 and CYP21 genes, which encode these P450 enzymes. Affected girls are born with ambiguous genitalia, but their circulating androgens are low, and virilisation does not progress. We aimed to investigate the underlying molecular basis of congenital adrenal hyperplasia with apparent combined P450C17 and P450C21 deficiency in affected children.<bold>Methods: </bold>We did sequence analysis of the human gene encoding P450 oxidoreductase, an enzyme that is important in electron transfer from NADPH to P450C17 and P450C21. We studied two unrelated families with a total of three affected children and 100 healthy controls. Wild-type and mutant P450 oxidoreductase proteins were bacterially expressed, purified, and assayed for cytochrome c reductase activity.<bold>Findings: </bold>We identified four mutations encoding single aminoacid changes in P450 oxidoreductase. All patients were compound heterozygotes, whereas their parents and an unaffected sibling harboured a mutation in only one allele. By contrast, no mutations were noted in the controls. Bacterial expression of recombinant mutant proteins revealed deficient or reduced enzyme activity.<bold>Interpretation: </bold>Molecular pathogenesis of this form of congenital adrenal hyperplasia is caused by mutations in the gene encoding P450 oxidoreductase. Deficiency of this enzyme could suggest an alternative pathway in human androgen synthesis, present only in fetal life, which explains the combination of antenatal androgen excess and postnatal androgen deficiency. [ABSTRACT FROM AUTHOR]
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  Data: <i>Copyright of Lancet is the property of Lancet and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Type: general
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