Characterization of novel StAR (steroidogenic acute regulatory protein) mutations causing non-classic lipoid adrenal hyperplasia

• Published in: PloS one Vol. 6; no. 5; p. e20178
• Main Authors: Flück, Christa E, Pandey, Amit V, Dick, Bernhard, Camats, Núria, Fernández-Cancio, Mónica, Clemente, María, Gussinyé, Miquel, Carrascosa, Antonio, Mullis, Primus E, Audi, Laura
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 27.05.2011; Public Library of Science (PLoS)
• Subjects: 46, XY Disorders of Sex Development - diagnosis; 46, XY Disorders of Sex Development - drug therapy; 46, XY Disorders of Sex Development - genetics; 46, XY Disorders of Sex Development - metabolism; Adolescent; Adrenal glands; Adrenal Hyperplasia, Congenital - diagnosis; Adrenal Hyperplasia, Congenital - drug therapy; Adrenal Hyperplasia, Congenital - genetics; Adrenal Hyperplasia, Congenital - metabolism; Adult; Age; Amino Acid Sequence; Amino acids; Animals; Base Sequence; Binding; Biology; Biomedical research; Biosynthesis; Blood proteins; Child; Children; Children & youth; Cholesterol; Cholesterol - metabolism; Congenital diseases; Endocrinology; Families & family life; Female; Gene mutation; Genes; Genetic aspects; Genetic disorders; Genitalia; Glucocorticoids; Glucocorticoids - deficiency; Health aspects; Heterozygote; Homozygote; Humans; Hyperplasia; Hypogonadism; In vitro methods and tests; Infant; Infant, Newborn; Lipids; Male; Medicine; Mitochondria; Models, Molecular; Molecular Sequence Data; Mutant Proteins - chemistry; Mutant Proteins - genetics; Mutant Proteins - metabolism; Mutation; Patients; Pediatrics; Phosphoproteins - chemistry; Phosphoproteins - genetics; Phosphoproteins - metabolism; Physiological aspects; Pregnancy; Protein Conformation; Protein structure; Proteins; Puberty; Receptor, Melanocortin, Type 2 - genetics; Siblings; Star protein; Stellar age; Steroid hormones; Steroidogenic acute regulatory protein; Steroids; Steroids (Organic compounds)
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0020178

Steroidogenic acute regulatory protein (StAR) is crucial for transport of cholesterol to mitochondria where biosynthesis of steroids is initiated. Loss of StAR function causes lipoid congenital adrenal hyperplasia (LCAH). StAR gene mutations causing partial loss of function manifest atypical and may be mistaken as familial glucocorticoid deficiency. Only a few mutations have been reported. To report clinical, biochemical, genetic, protein structure and functional data on two novel StAR mutations, and to compare them with published literature. Collaboration between the University Children's Hospital Bern, Switzerland, and the CIBERER, Hospital Vall d'Hebron, Autonomous University, Barcelona, Spain. Two subjects of a non-consanguineous Caucasian family were studied. The 46,XX phenotypic normal female was diagnosed with adrenal insufficiency at the age of 10 months, had normal pubertal development and still has no signs of hypergonodatropic hypogonadism at 32 years of age. Her 46,XY brother was born with normal male external genitalia and was diagnosed with adrenal insufficiency at 14 months. Puberty was normal and no signs of hypergonadotropic hypogonadism are present at 29 years of age. StAR gene analysis revealed two novel compound heterozygote mutations T44HfsX3 and G221S. T44HfsX3 is a loss-of-function StAR mutation. G221S retains partial activity (∼30%) and is therefore responsible for a milder, non-classic phenotype. G221S is located in the cholesterol binding pocket and seems to alter binding/release of cholesterol. StAR mutations located in the cholesterol binding pocket (V187M, R188C, R192C, G221D/S) seem to cause non-classic lipoid CAH. Accuracy of genotype-phenotype prediction by in vitro testing may vary with the assays employed.