title: Congenital lipoid adrenal hyperplasia caused by a novel splicing mutation in the gene for the steroidogenic acute regulatory protein.
abstract: Steroidogenic acute regulatory protein (StAR) plays a crucial role in the transport of cholesterol from the cytoplasm to the inner mitochondrial membrane, facilitating its conversion to pregnenolone by cytochrome P450scc. Its essential role in steroidogenesis was demonstrated after observing that StAR gene mutations gave rise to a potentially lethal disease named congenital lipoid adrenal hyperplasia, in which virtually no steroids are produced. We report here a 2-month-old female patient, karyotype 46XY, who presented with growth failure, convulsions, dehydration, hypoglycemia, hyponatremia, hypotension, and severe hyperpigmentation suggestive of adrenal insufficiency. Serum cortisol, 17OH-progesterone, dehydroepiandrosterone sulfate, testosterone, 17OH-pregnenolone, and aldosterone levels were undetectable in the presence of high ACTH and plasma renin activity levels. Immunohistochemical analysis of testis tissues revealed the absence of StAR protein. Molecular analysis of StAR gene demonstrated a homozygous G to T mutation within the splice donor site of exon 1 (IVS1 + 1G>T). Her parents and one brother were heterozygous for this mutation. In vitro analysis of the mutation was performed in COS cells transfected with minigenes coding regions spanning exon-intron 1 to 3 carrying the mutant and the wild-type sequences. RT-PCR analyses of the mutant gene showed an abnormal mRNA transcript of 2430 bp (normal size 433 bp). Sequence analysis of the mutant mRNA demonstrated the retention of intron 1. Immunolocalization of the StAR minigene product detected the peptide in the mitochondria of COS cells transfected with the wild-type minigene but not in those transfected with the mutant minigene. We conclude that this mutation gives rise to a truncated StAR protein, which lacks an important N-terminal region and the entire lipid transfer domain.
authors.affiliation: Department of Endocrinology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago.
authors.forename: Alexis A
authors.initials: AA
authors.lastname: González
authors.forename: M Loreto
authors.initials: ML
authors.lastname: Reyes
authors.forename: Cristian A
authors.initials: CA
authors.lastname: Carvajal
authors.forename: Jaime A
authors.initials: JA
authors.lastname: Tobar
authors.forename: Lorena M
authors.initials: LM
authors.lastname: Mosso
authors.forename: Paulina
authors.initials: P
authors.lastname: Baquedano
authors.forename: Antonieta
authors.initials: A
authors.lastname: Solar
authors.forename: Alejandro
authors.initials: A
authors.lastname: Venegas
authors.forename: Carlos E
authors.initials: CE
authors.lastname: Fardella
mesh_terms: D000312:Adrenal Hyperplasia, Congenital / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001483:Base Sequence / Q000235:genetics; D019556:COS Cells; D002522:Chlorocebus aethiops; D004262:DNA Restriction Enzymes; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D008969:Molecular Sequence Data; D009154:Mutation; D010750:Phosphoproteins / Q000235:genetics*; D012326:RNA Splicing; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014018:Tissue Distribution; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: D010750:Phosphoproteins; D000098682:Steroidogenic Acute Regulatory Protein; D004262:DNA Restriction Enzymes