Buss et al. (2007) identified a heterozygous 1254G-T transversion in the SERPINA6 gene, resulting in the D367N substitution, in a 22-year-old Swiss male patient with severe muscle fatigue, usually after stressful events. Extensive biochemical and endocrine analysis showed decreased serum CBG and increased serum cortisol in response to ACTH or catecholamine administration. Investigation of other family members showed that the mutation occurred de novo on the paternal allele. Buss et al. (2007) proposed that SERPINA6 deficiency may act as an autosomal dominant disorder with incomplete penetrance, although a second pathogenic mutation could not be excluded.

Steroid hormones activate target cells through specific receptors that discriminate among ligands based upon recognition of distinct structural features. For most known steroids, membrane and nuclear receptors co-exist in many target cells. However, while the structure of the nuclear receptors and their function as transcriptional activators of specific target genes is generally well understood, the identity of the membrane receptors remains elusive. Using pharmacological and biochemical approaches, we are beginning to characterize receptors for glucocorticoids and anabolic-androgenic steroids in male rat liver membranes. Male rat liver endoplasmic reticulum contains two steroid binding sites which are functionally related and associated with a 90–134   kDa oligomeric protein: (1) the low-affinity glucocorticoid binding site (LAGS), composed at least in part of two peptides (37 and 53   kDa) that bind glucocorticoids and (2) the stanozolol binding protein (STBP), composed at least in part of three peptides (22, 31, and 55   kDa) that bind the synthetic androgen stanozolol. These steroid binding proteins have many properties different from those of classical nuclear receptors, with the salient differences being a failure to recognize “classical” ligands for nuclear receptors together with marked differences in biochemical properties and physiological regulation. The mechanism of interaction of glucocorticoids with the LAGS can be clearly distinguished from that with STBP. Moreover, STBP shows an extremely narrow pharmacological profile, being selective for ST and its analog, danazol, among more than 100 steroids and non-steroidal compounds that were assayed, including those that are able to displace glucocorticoids from the LAGS. The level of LAGS activity undergoes dramatic variations following changes from the physiological serum levels of thyroid hormones, glucocorticoids, GH, vitamin A, and E2. However, neither thyroid hormones nor GH have a critical role on STBP activity. The STBP is functionally related to LAGS. We have suggested a novel mechanism for STBP whereby membrane-associated glucocorticoid binding activity is targeted by stanozolol (and 16β-hydroxylated stanozolol): stanozolol modulates glucocorticoid activity in the liver through negative allosteric modulation of the LAGS resulting in an effective increase in classical GR-signaling by increasing glucocorticoid availability to the cytosolic GR.

Protein S can bind to negatively charged phospholipids via the carboxylated Gla domain. This property allows Protein S to function in the removal of cells which are undergoing apoptosis . Apoptosis is a form of cell death that is used by the body to remove unwanted or damaged cells from tissues. Cells, which are apoptotic (. in the process of apoptosis ), no longer actively manage the distribution of phospholipids in their outer membrane and hence begin to display negatively charged phospholipids, such as phosphatidyl serine, on the cell surface. In healthy cells, an ATP ( Adenosine triphosphate )-dependent enzyme removes these from the outer leaflet of the cell membrane. These negatively charged phospholipids are recognized by phagocytes such as macrophages . Protein S can bind to the negatively charged phospholipids and function as a bridging molecule between the apoptotic cell and the phagocyte. The bridging property of Protein S enhances the phagocytosis of the apoptotic cell, allowing it to be removed 'cleanly' without any symptoms of tissue damage such as inflammation occurring.