Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0015672 (fatigue)
 51,768 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Corticosteroid-binding globulin (SERPINA6) deficiency is an extremely rare hereditary disorder characterized by reduced corticosteroid-binding capacity with normal or low plasma corticosteroid-binding globulin concentration, and normal or low basal cortisol levels associated with hypo-/hypertension and muscle fatigue. Here, we present a patient with severe muscle fatigue, normal blood pressure, and abnormal high saliva cortisol levels following a standardized stress test. This patient was found heterozygous for a de novo 367 asparagine-encoding variant of the corticosteroid-binding globulin gene, previously described as "transcortin Lyon". Both parents were homozygous for the ("wildtype") 367 aspartate-encoding allele. To the best of our knowledge, this case represents the first de novo mutation reported for corticosteroid-binding globulin deficiency, implicating a pathogenic role of variants of SERPINA6 in some cases of muscle fatigue.
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PMID:Haploinsufficiency of the SERPINA6 gene is associated with severe muscle fatigue: A de novo mutation in corticosteroid-binding globulin deficiency. 1724 37

Corticosteroid-binding globulin (CBG, transcortin) belongs to the serpin family of serine protease inhibitors (SERPINA6) and is mainly secreted by the liver. The negative acute phase protein CBG regulates free cortisol levels in the blood and distributes cortisol to its target tissues. So far no CBG serpin partner protease has been identified. However, its cleavage by human neutrophil elastase destroys ligand binding capacity and supposedly liberates cortisol at sites of inflammation. Here we report on the recombinant expression and secretion of human wild-type CBG and several novel mutants by human 293-EBNA cells. Functional characterization of wild-type and mutant CBG revealed distinct differences in ligand binding sensitivity to heat or elastase. Certain mutants are almost devoid of cortisol binding activity (Q232R and CBG Lyon), some display higher sensitivity for heat inactivation (G335V, Q232R and CBG Lyon) or for elastase cleavage (G335V). CBG mutant T342A is more resistant to elastase cleavage. Our data support the validity of the serpin structural concept. The expression system used provides functionally active human recombinant transcortin for further functional characterization of wild-type and human CBG mutant variants, which have been associated with altered serum free cortisol levels or pathophysiological constellations such as increased body weight, fatigue or hypotension.
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PMID:Effect of mutations of the human serpin protein corticosteroid-binding globulin on cortisol-binding, thermal and protease sensitivity. 2022 61