Clinical and functional analyses of the novel STAR c.558C>A in a patient with classic lipoid congenital adrenal hyperplasia

Abstract

Objective: Congenital lipid adrenal hyperplasia (LCAH) is the most serious type of congenital adrenal hyperplasia and is caused by steroid-based acute regulatory (STAR) protein mutations. Herein, we report compound heterozygous mutations c.558C>A (p.S186 R) and c.772C>T (p.Q258*) in a newborn 46 XY patient diagnosed with classic LCAH and explore their clinical and functional characteristics.Methods: Peripheral blood samples were collected from LCAH patient and their families. The pathogenic variant identified by whole-exome sequencing was further confirmed by Sanger sequencing and pedigree verification. The functional consequence and ability to convert cholesterol into progesterone of the identified STAR Q258* and S186 R mutations were analyzed by cell transfection and in vitro assays.Results: The proband was presented with severe glucocorticoid and mineralocorticoid deficiency, high adrenocorticotropic hormone, and enlarged adrenals. Heterozygous mutations p. S186 R and p. Q258* in the STAR gene were identified in the patient, and her parents were carriers, which is consistent with an autosomal recessive disorder. The STAR p. Q258* mutation has been reported and generates a truncated protein. The p. S186 R mutation is a novel variant that disrupts STAR. The residual STAR activities of p. S186R, p. Q258*, and p. S186R/p.Q258* were 13.9%, 7.3%, and 11.2%, respectively, of the wild-type, proving the main negative effects of the mutant proteins.Conclusion: Our findings reveal the molecular mechanisms underlying LCAH pathogenesis, further expanding the genotype and clinical spectrum of LCAH.

Molecular tools for diagnosing diseases of the adrenal cortex

“…Regarding molecular dysfunction, dysregulation of genes encoding steroidogenesis enzymes and cofactors, such as CYP21A2, is the leading cause of CAH. In rare cases, pathogenic variations in STAR, CYP11A1, HSD3B2, CYPB11B1, CYP17A1, and POR, involved in the biosynthesis of glucocorticoids, can also lead to CAH [12]. This review will not discuss molecular diagnosis of CAH which is described extensively in several recent reports.…”

Familial Glucocorticoid Deficiency: the changing landscape of an eponymous syndrome

“…Progressive lipid accumulation leads to mitochondrial oxidative damage and cellular stress ultimately abolishing residual STAR-independent steroidogenic capacity (48, 49). Early fetal destruction of Leydig cell integrity in 46,XY subjects leads to lack of testosterone and feminized external genitalia (50). The fetal ovary, on the contrary, is relatively preserved until puberty when gonadotrophin stimulation leads to cholesterol accumulation.…”