A Genetic Isolate of Congenital Lipoid Adrenal Hyperplasia with Atypical Clinical Findings

Abstract

Congenital lipoid adrenal hyperplasia (lipoid CAH) is the most severe form of CAH, eventually destroying all adrenal and gonadal steroidogenesis. Lipoid CAH is caused by mutations in the steroidogenic acute regulatory protein (StAR), which facilitates the entry of cholesterol into mitochondria to initiate steroidogenesis. Patients with lipoid CAH typically present with a salt-losing crisis in the first 2 months of life, although presentation as late as 10 months with partial retention of StAR activity has been reported. We describe eight patients from six Saudi Arabian families who were first diagnosed at 1-14 months of age (median, 4-7 months; mean, 7 months). Five patients were 46,XY, and three were 46,XX. At presentation, all had hyponatremia, hyperkalemia, elevated ACTH, and low cortisol. Pregnenolone, progesterone, 17-hydroxypregnenolone, 17-hydroxyprogesterone, testosterone, androstenedione, and dehydroepiandrosterone sulfate were all low in those patients in whom it was measured. DNA sequencing showed that one patient was homozygous for the StAR mutation M144R, and the other seven, from five apparently unrelated families, were homozygous for the StAR mutation R182H. Each mutation was recreated in a human StAR cDNA expression vector and found to be wholly inactive in a standard assay of COS-1 cells cotransfected with the cholesterol side-chain cleavage enzyme system. Thus, the loss of all assayable activity in vitro correlated poorly with the later onset of clinical symptoms in these patients. Lipoid CAH may present much later in life than previously thought.

A pH-dependent Molten Globule Transition Is Required for Activity of the Steroidogenic Acute Regulatory Protein, StAR

“…The engineered disulfide bond in the SS mutant is in the middle of the C-helix (S261C), which only partially restricted movement of this helix. Binding by DA was similar to the buffer background or binding by the inactive StAR mutant M144R (9). The DA mutant contains a disulfide closer to the carboxyl terminus (A268C), which more completely immobilized the C-helix and eliminated all measurable cholesterol binding.…”

“…Steroidogenic acute regulatory protein (StAR), 3 which is essential for normal adrenal and gonadal steroidogenesis, facilitates the flow of cholesterol from the outer mitochondrial membrane (OMM) to the inner mitochondrial membrane (IMM), where cholesterol is converted to pregnenolone by the cholesterol side chain cleavage enzyme, P450scc (3,4). Mutation of human StAR causes potentially lethal congenital lipoid adrenal hyperplasia (5,6); all missense mutations that cause this disease are found in the carboxyl-terminal 50% of the protein, indicating that these sequences are required for StAR activity (7)(8)(9). StAR is synthesized as a 37-kDa phosphoprotein with an amino-terminal mitochondrial leader sequence that is cleaved during mitochondrial entry (3,10,11).…”

High allele frequency of the p.Q258X mutation and identification of a novel mis-splicing mutation in the STAR gene in Korean patients with congenital lipoid adrenal hyperplasia

“…The p.R182H mutation has been previously reported, and many of the patients bearing this mutation have clinically milder and later onset CLAH symptoms (8). This mutation changes the strong basic arginine residue to the weak basic histidine.…”

“…The incidence of certain mutations is very high in specific ethnic groups. Genetic clusters consistently identified to date include the p.Q258X mutation in the Japanese and Korean populations (5,6), the p.R182L mutation among Palestinian Arabs (7), the p.R182H mutation in eastern Saudi Arabia (8), and the p.L260P mutation in the Swiss population (9). However, in most Palestinian cases, a founder c.201_202delCT mutation in STAR is the most common (10); the p.R182L mutation has also been described in a Japanese patient (11).…”

Replacement of Alanine with Asparagic Acid at Position 203 in Human Steroidogenic Acute Regulatory Protein Impairs the Ability to Enhance Steroidogenesis in vitro

“…To date, a variety of mutations in the STAR gene have been reported in patients with CLAH [2,[4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. We also reported a D203A polymorphism in the STAR gene in Japanese patients with CLAH as well as in normal Japanese subjects [12].…”