Effect of mutations of the human serpin protein corticosteroid-binding globulin on cortisol-binding, thermal and protease sensitivity

Braun, Beate C.; Meyer, Hellmuth-A.; Reetz, Antje; Fuhrmann, Ulrike; Köhrle, Josef

doi:10.1016/j.jsbmb.2010.03.014

Cited by 7 publications

(7 citation statements)

References 41 publications

(69 reference statements)

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“…This is consistent with other findings [17]. On the other hand, as expected, cleaved CBG was not recognised by the RCL monoclonal antibody as the epitope exactly spanned the elastase cleavage site.…”

Section: Discussionsupporting

confidence: 93%

“…Elastase cleaved CBG with substitutions at the P16 residue (Glu 334 Gly or Glu 334 Ala) that show complete loss of cortisol binding [7] may not be expected to be recognised by these RCL monoclonal antibodies and other human CBG mutants with differences in ligand binding sensitivity to heat or elastase [17] are also likely candidates for the use of these novel RCL antibodies. Similarly the investigation of the temperature dependent release of cortisol from CBG could prove useful as the reactive centre loop region is temperature responsive [19].…”

Section: Discussionmentioning

confidence: 99%

“…We cannot rule out the possibility that the discordance in plasma CBG levels, in these two apparently healthy adults, was not due to a mutation resulting in partial inaccessibility to the RCL region by antibody 9G12. However we consider this possibility less likely as the only known natural CBG mutation proximal to the RCL loop, CBG Lyon Asp 367 Asn [20], is sensitive to elastase cleavage [17] implying adequate loop exposure. We were unable to test the two discordant plasma samples for elastase sensitivity as they were depleted.…”

Section: Discussionmentioning

confidence: 99%

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Corticosteroid-binding globulin reactive centre loop antibodies recognise only the intact natured protein: Elastase cleaved and uncleaved CBG may coexist in circulation

Lewis

Elder

2011

The Journal of Steroid Biochemistry and Molecular Biology

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Corticosteroid-binding globulin reactive centre loop antibodies recognise only the intact natured protein: Elastase cleaved and uncleaved CBG may coexist in circulation

Lewis

Elder

2011

The Journal of Steroid Biochemistry and Molecular Biology

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“…SerpinA6 , also known as cortisol binding globulin or transcortin has been shown to alter cortisol binding and degradation when mutated. 17 This finding lends biologic plausibility to genetic variation in SerpinA6 being associated with altered cortisol effectiveness and risk of RDS and respiratory impairment.…”

Section: Discussionmentioning

confidence: 84%

Neonatal Genetic Variation in Steroid Metabolism and Key Respiratory Function Genes and Perinatal Outcomes in Single and Multiple Courses of Corticosteroids

et al. 2015

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OBJECTIVE-To evaluate the association of steroid metabolism and respiratory gene polymorphisms in neonates exposed to antenatal corticosteroids (ACS) with respiratory outcomes, small for gestational age (SGA) and response to repeat ACS.STUDY DESIGN-This candidate gene study is a secondary analysis of women enrolled in a randomized controlled trial of single versus weekly courses of ACS. Nineteen single nucleotide polymorphisms (SNPs) in 13 steroid metabolism and respiratory function genes were evaluated. DNA was extracted from placenta or fetal cord serum and analyzed with TaqMan genotyping. Each SNP was evaluated for association via logistic regression with respiratory distress syndrome (RDS), CPAP/ventilator use (CPV) and SGA.RESULTS-CRHBP, CRH and CRHR1 minor alleles were associated with an increased risk of SGA. HSD11B1 and SCNN1B minor alleles were associated with an increased likelihood of RDS. Carriage of minor alleles in SerpinA6 was associated with an increased risk of CPV. CRH and CRHR1 minor alleles were associated with a decreased likelihood of CPV. HHS Public AccessAuthor manuscript Am J Perinatol. Author manuscript; available in PMC 2016 May 07.CONCLUSION-Steroid metabolism and respiratory gene SNPs are associated with respiratory outcomes and SGA in patients exposed to ACS. Risks for respiratory outcomes are affected by minor allele carriage as well as by treatment with multiple ACS.

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“…Total plasma cortisol was low after stimulation with synthetic adrenocorticotropic hormone (ACTH); however, 24-h urinary free cortisol excretion was normal. Elevated plasma-free Table 4) [ 66,96]. Interestingly these studies have shown that mutations, particularly within the RCL at threonine 342 confer resistance to protease cleavage [96].…”

Section: Human Observationsmentioning

confidence: 99%

Corticosteroid-Binding Globulin: A Review of Basic and Clinical Advances

et al. 2016

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Corticosteroid-binding globulin (CBG, transcortin) is the primary cortisol binding protein. It is a non-inhibitory serine protease inhibitor, capable of conformational change from a high cortisol-binding affinity form to a low affinity form upon cleavage of its reactive centre loop by various proteases, such as neutrophil elastase. The burgeoning inflammatory role of CBG applies to acute, severe inflammation where depletion is associated with mortality, and to chronic inflammation where defects in cortisol delivery may perpetuate inflammation. Naturally occurring human mutations influence a wide range of CBG properties and point toward a role in hitherto unexplained chronic musculoskeletal pain and fatigue disorders as well as potentially affecting fertility outcomes including offspring gender. In vitro and knock-out animal models of CBG propose a role for CBG in cortisol transport to the brain, providing a foundation for understanding the human observations in those with CBG mutations and sex differences in stress-related mood and behaviour. Finally, CBG measurement has a practical role in the estimation of free cortisol, useful in clinical circumstances where CBG levels or cortisol binding affinity is reduced. Taken together, novel data suggest a role for cortisol in targeted cortisol delivery, with implications in acute and chronic inflammation, as well as roles in metabolism and neurocognitive function, implying that CBG is a multifaceted component in the mechanisms of hypothalamic-pituitary-adrenal axis related homeostasis.

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Effect of mutations of the human serpin protein corticosteroid-binding globulin on cortisol-binding, thermal and protease sensitivity

Cited by 7 publications

References 41 publications

Corticosteroid-binding globulin reactive centre loop antibodies recognise only the intact natured protein: Elastase cleaved and uncleaved CBG may coexist in circulation

Corticosteroid-binding globulin reactive centre loop antibodies recognise only the intact natured protein: Elastase cleaved and uncleaved CBG may coexist in circulation

Neonatal Genetic Variation in Steroid Metabolism and Key Respiratory Function Genes and Perinatal Outcomes in Single and Multiple Courses of Corticosteroids

Corticosteroid-Binding Globulin: A Review of Basic and Clinical Advances

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