Mutations in the genes encoding 11β-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase interact to cause cortisone reductase deficiency

Nicole Draper, Elizabeth A. Walker, Iwona J. Bujalska, Jeremy W. Tomlinson, Susan M. Chalder, Wiebke Arlt, Gareth G. Lavery, Oliver Bedendo, David W. Ray, Ian Laing, Ewa Malunowicz, Perrin C. White, Martin Hewison, Philip J. Mason, John M. Connell, Cedric H L Shackleton, Paul M. Stewart

Research output: Contribution to journalArticle

236 Citations (Scopus)

Abstract

In cortisone reductase deficiency (CRD), activation of cortisone to cortisol does not occur, resulting in adrenocorticotropin-mediated androgen excess and a phenotype resembling polycystic ovary syndrome (PCOS; refs. 1,2). This suggests a defect in the gene HSD11B1 encoding 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), a primary regulator of tissue-specific glucocorticoid bioavailability. We identified intronic mutations in HSD11B1 that resulted in reduced gene transcription in three individuals with CRD. In vivo, 11β-HSD1 catalyzes the reduction of cortisone to cortisol whereas purified enzyme acts as a dehydrogenase converting cortisol to cortisone. Oxo-reductase activity can be regained using a NADPH-regeneration system and the cytosolic enzyme glucose-6-phosphate dehydrogenase. But the catalytic domain of 11β-HSD1 faces into the lumen of the endoplasmic reticulum (ER; ref. 6). We hypothesized that endolumenal hexose-6-phosphate dehydrogenase (H6PDH) regenerates NADPH in the ER, thereby influencing directionality of 11β-HSD1 activity. Mutations in exon 5 of H6PD in individuals with CRD attenuated or abolished H6PDH activity. These individuals have mutations in both HSD11B1 and H6PD in a triallelic digenic model of inheritance, resulting in low 11β-HSD1 expression and ER NADPH generation with loss of 11β-HSD1 oxoreductase activity. CRD defines a new ER-specific redox potential and establishes H6PDH as a potential factor in the pathogenesis of PCOS.

Original languageEnglish (US)
Pages (from-to)434-439
Number of pages6
JournalNature Genetics
Volume34
Issue number4
DOIs
StatePublished - Aug 1 2003

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11-beta-Hydroxysteroid Dehydrogenases
Mutation
Cortisone
NADP
Genes
Hydrocortisone
Oxidoreductases
Glucosephosphate Dehydrogenase
Polycystic Ovary Syndrome
Enzymes
Endoplasmic Reticulum
Adrenocorticotropic Hormone
Glucocorticoids
Biological Availability
Androgens
Oxidation-Reduction
Cortisone reductase deficiency
galactose-6-phosphate dehydrogenase
Regeneration
Exons

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Mutations in the genes encoding 11β-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase interact to cause cortisone reductase deficiency. / Draper, Nicole; Walker, Elizabeth A.; Bujalska, Iwona J.; Tomlinson, Jeremy W.; Chalder, Susan M.; Arlt, Wiebke; Lavery, Gareth G.; Bedendo, Oliver; Ray, David W.; Laing, Ian; Malunowicz, Ewa; White, Perrin C.; Hewison, Martin; Mason, Philip J.; Connell, John M.; Shackleton, Cedric H L; Stewart, Paul M.

In: Nature Genetics, Vol. 34, No. 4, 01.08.2003, p. 434-439.

Research output: Contribution to journalArticle

Draper, N, Walker, EA, Bujalska, IJ, Tomlinson, JW, Chalder, SM, Arlt, W, Lavery, GG, Bedendo, O, Ray, DW, Laing, I, Malunowicz, E, White, PC, Hewison, M, Mason, PJ, Connell, JM, Shackleton, CHL & Stewart, PM 2003, 'Mutations in the genes encoding 11β-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase interact to cause cortisone reductase deficiency', Nature Genetics, vol. 34, no. 4, pp. 434-439. https://doi.org/10.1038/ng1214
Draper, Nicole ; Walker, Elizabeth A. ; Bujalska, Iwona J. ; Tomlinson, Jeremy W. ; Chalder, Susan M. ; Arlt, Wiebke ; Lavery, Gareth G. ; Bedendo, Oliver ; Ray, David W. ; Laing, Ian ; Malunowicz, Ewa ; White, Perrin C. ; Hewison, Martin ; Mason, Philip J. ; Connell, John M. ; Shackleton, Cedric H L ; Stewart, Paul M. / Mutations in the genes encoding 11β-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase interact to cause cortisone reductase deficiency. In: Nature Genetics. 2003 ; Vol. 34, No. 4. pp. 434-439.
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abstract = "In cortisone reductase deficiency (CRD), activation of cortisone to cortisol does not occur, resulting in adrenocorticotropin-mediated androgen excess and a phenotype resembling polycystic ovary syndrome (PCOS; refs. 1,2). This suggests a defect in the gene HSD11B1 encoding 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), a primary regulator of tissue-specific glucocorticoid bioavailability. We identified intronic mutations in HSD11B1 that resulted in reduced gene transcription in three individuals with CRD. In vivo, 11β-HSD1 catalyzes the reduction of cortisone to cortisol whereas purified enzyme acts as a dehydrogenase converting cortisol to cortisone. Oxo-reductase activity can be regained using a NADPH-regeneration system and the cytosolic enzyme glucose-6-phosphate dehydrogenase. But the catalytic domain of 11β-HSD1 faces into the lumen of the endoplasmic reticulum (ER; ref. 6). We hypothesized that endolumenal hexose-6-phosphate dehydrogenase (H6PDH) regenerates NADPH in the ER, thereby influencing directionality of 11β-HSD1 activity. Mutations in exon 5 of H6PD in individuals with CRD attenuated or abolished H6PDH activity. These individuals have mutations in both HSD11B1 and H6PD in a triallelic digenic model of inheritance, resulting in low 11β-HSD1 expression and ER NADPH generation with loss of 11β-HSD1 oxoreductase activity. CRD defines a new ER-specific redox potential and establishes H6PDH as a potential factor in the pathogenesis of PCOS.",
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AU - Lavery, Gareth G.

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AU - Laing, Ian

AU - Malunowicz, Ewa

AU - White, Perrin C.

AU - Hewison, Martin

AU - Mason, Philip J.

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