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    Novel corticosteroid-binding globulin variant that lacks steroid binding activity.

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    Authors
    Perogamvros, Ilias
    Underhill, C
    Henley, D E
    Hadfield, K D
    Newman, W G
    Ray, David W
    Lightman, S L
    Hammond, G L
    Trainer, Peter J
    Affiliation
    Department of Endocrinology, Christie Hospital, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom.
    Issue Date
    2010-10
    
    Metadata
    Show full item record
    Abstract
    BACKGROUND: Corticosteroid-binding globulin (CBG) is the principal carrier for glucocorticoids in the circulation and a regulator of their bioavailability. Inherited CBG deficiencies are rarely reported, and only three causative mutations in four families have been described. PATIENTS, METHODS, AND RESULTS: In a 26-yr-old female with hypotension, fatigue, and undetectable total serum cortisol at presentation, we have identified a novel homozygous c.776g>t transversion in exon 3 of the CBG (SERPINA6) gene. This results in a p.Gly237Val substitution that is predicted to influence the positioning of two β-sheets that constitute part of the CBG steroid-binding site. Two siblings were also homozygous for the variant, whereas her mother and an unaffected sibling were heterozygous. No other symptomatic family members were identified apart from the proband. Individuals homozygous for the variant had serum CBG levels below the reference range when measured by RIA, but CBG was unmeasurable in cortisol-binding capacity assays. In the same individuals, we observed very low baseline and stimulated total serum cortisol levels but normal free serum and salivary cortisol and plasma ACTH. In a study of ultradian cortisol pulsatility, increased pulse frequency was only observed in the proband. CONCLUSION: We describe a novel CBG variant that lacks steroid binding activity. All mutant homozygotes have very low total serum cortisol, but normal free serum cortisol levels. The only biochemical feature to distinguish the symptomatic subject was increased cortisol pulsatility, and we suggest that this may influence glucocorticoid signaling and contribute to symptoms previously associated with CBG deficiency.
    Citation
    Novel corticosteroid-binding globulin variant that lacks steroid binding activity. 2010, 95 (10):E142-50 J Clin Endocrinol Metab
    Journal
    The Journal of Clinical Endocrinology and Metabolism
    URI
    http://hdl.handle.net/10541/115810
    DOI
    10.1210/jc.2010-0746
    PubMed ID
    20610591
    Type
    Article
    Language
    en
    ISSN
    1945-7197
    ae974a485f413a2113503eed53cd6c53
    10.1210/jc.2010-0746
    Scopus Count
    Collections
    All Christie Publications
    Endocrinology

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