Hereditary corticosteroid‐binding globulin deficiency due to a missense mutation (Asp367Asn, CBG Lyon) in a Brazilian kindred

Abstract

An abnormal CBG resulting from a missense mutation and known as CBG Lyon was found in this Brazilian kindred. This abnormal CBG has decreased affinity for cortisol and results in low or low normal serum cortisol levels in homozygous and heterozygous subjects. Although relative hypotension and fatigue have recently been associated with CBG deficiency in a family with two CBG mutations (null and Lyon), the two homozygous subjects in this kindred were both normotensive and only the proband presented with fatigue.

Hyporesponsiveness to Glucocorticoids in Mice Genetically Deficient for the Corticosteroid Binding Globulin

“…However, total hormone levels are lower than in healthy subjects, so that the overall concentration of the circulating free hormone remains within the normal range (35). Thus, the overall effect of CBG deficiency on normal body function is modest, with some families exhibiting fatigue and hypotension (35) while other families do not (4).…”

“…Known mutations in the human cbg gene result in amino acid changes that significantly reduce cortisol binding affinity (CBG Lyon, transcortin Leuven) (4,31,37) or that cause stop mutations, leading to premature termination of translation and the absence of CBG immunoreactivity in plasma (35). Individuals that are homozygous for the null mutation have drastically reduced total cortisol levels (1.8 g/dl; reference range, 5 to 14 g/dl), and exhibit a prevalence of fatigue (35).…”

Functional Implication of an Arg307Gly Substitution in Corticosteroid-Binding Globulin, a Candidate Gene for a Quantitative Trait Locus Associated With Cortisol Variability and Obesity in Pig

“…However, this effect was significant in two of three transfection assays. Genetic variants of CBG have been reported in rat (Smith and Hammond 1991), in mouse (Orava et al 1994), and in humans (Van Baelen et al 1982;Smith et al 1992;Emptoz-Bonneton et al 2000;Brunner et al 2003). The alignment of pig and rat amino acid sequences shows that the pig Arg307 amino acid is located at two residues of the substitution Met276Ile in the rat that is implicated in reduced steroid binding affinity of the BioBreeding rat (Smith and Hammond 1991).…”

Corticosteroid-Binding Globulin Gene Mutations and Chronic Fatigue/Pain Syndromes: An Overview of Current Evidence

“…Since then, CBG Lyon has been described in two other kindreds 82,85 . The mutation has been reported in a 40 year-old white Brazilian woman presenting with chronic fatigue and hypotension.…”

“…The mutation has been reported in a 40 year-old white Brazilian woman presenting with chronic fatigue and hypotension. The family members screened, including her parents and her children, were found to be heterozygous for the mutation but did not complain of chronic fatigue 85 . We have also reported CBG Lyon mutation in the family members of a proband with CBG null mutation 82 .…”