Lipoid congenital adrenal hyperplasia due to STAR mutations in a Caucasian patient.

Unlabelled: Lipoid congenital adrenal hyperplasia (lipoid CAH), the most severe form of CAH, is most commonly caused by mutations in steroidogenic acute regulatory protein (STAR), which is required for the movement of cholesterol from the outer to the inner mitochondrial membranes to synthesize pregnenolone. This study was performed to evaluate whether the salt-losing crisis and the adrenal inactivity experienced by a Scandinavian infant is due to a de novo STAR mutation. The study was conducted at the University of North Dakota, the Mercer University School of Medicine and the Memorial University Medical Center to identify the cause of this disease.

Passenger protein determines translocation versus retention in the endoplasmic reticulum for aromatase expression.

Aromatase protein is overexpressed in the breasts of women affected with cancer. In the endoplasmic reticulum (ER), signal sequence and signal anchors (SAs) facilitate translocation and topology of proteins. To understand the function of type-I SAs (SA-Is), we evaluated translocation of aromatase, whose signal anchor follows a hydrophilic region.

Alteration in accumulated aldosterone synthesis as a result of N-terminal cleavage of aldosterone synthase.

Aldosterone synthase (AS) regulates blood volume by synthesizing the mineralocorticoid aldosterone. Overproduction of aldosterone in the adrenal gland can lead to hypertension, a major cause of heart disease and stroke. Aldosterone production depends upon stimulation of AS expression by the renin-angiotensin system, which takes 12 h to reach full effect, and then 24 h to subside.

Lipid-mediated unfolding of 3β-hydroxysteroid dehydrogenase 2 is essential for steroidogenic activity.

For inner mitochondrial membrane (IMM) proteins that do not undergo N-terminal cleavage, the activity may occur in the absence of a receptor present in the mitochondrial membrane. One such protein is human 3β-hydroxysteroid dehydrogenase 2 (3βHSD2), the IMM resident protein responsible for catalyzing two key steps in steroid metabolism: the conversion of pregnenolone to progesterone and dehydroepiandrosterone to androstenedione. Conversion requires that 3βHSD2 serve as both a dehydrogenase and an isomerase.

Decreased cytochrome c oxidase IV expression reduces steroidogenesis.

Steroidogenic acute regulatory protein facilitates the translocation of cholesterol to the inner mitochondrial membrane, thereby initiating steroidogenesis. At the inner mitochondrial membrane, cytochrome P450 side-chain cleavage enzyme converts cholesterol to pregnenolone, an oxidative process requiring electrons from NADPH. Pregnenolone then serves as the substrate for the formation of progesterone or dehydroepiandrosterone by downstream enzymes.

Steroidogenic acute regulatory protein has a more open conformation than the independently folded smaller subdomains.

The acute steroidogenic response, which produces steroids in response to stress, requires the steroidogenic acute regulatory protein (StAR). StAR, a mitochondrial matrix protein, acts on the outer mitochondrial membrane (OMM) to facilitate the movement of cholesterol from the outer to inner mitochondrial membrane via an unknown mechanism. The N-terminal sequence was reported to be nonessential for activity.