Characterization of Novel StAR (Steroidogenic Acute Regulatory Protein) Mutations Causing Non-Classic Lipoid Adrenal Hyperplasia

Christa E Flück,Antonio Carrascosa,Amit V Pandey,Mónica Fernández-Cancio,Miquel Gussinyé,Primus E Mullis,Laura Audi,Bernhard Dick,María Clemente,Núria Camats,Ingrid A Dahlman

doi:10.1371/journal.pone.0020178

Abstract

ContextSteroidogenic 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).ObjectiveStAR gene mutations causing partial loss of function manifest atypical and may be mistaken as familial glucocorticoid deficiency. Only a few mutations have been reported.DesignTo report clinical, biochemical, genetic, protein structure and functional data on two novel StAR mutations, and to compare them with published literature.SettingCollaboration between the University Children's Hospital Bern, Switzerland, and the CIBERER, Hospital Vall d'Hebron, Autonomous University, Barcelona, Spain.PatientsTwo 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.ResultsStAR 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.ConclusionsStAR 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.

Highlights

Mutations in the Steroidogenic acute regulatory protein (StAR) gene were first described in patients with classic congenital lipoid adrenal hyperplasia (CLAH) in which both the adrenals and the gonads seemed to completely lack steroidogenesis [1]
familial glucocorticoid deficiency (FGD) has been described as a syndrome secondary to ACTH resistance, and inactivating mutations in the gene encoding melanocortin type 2 receptor (MC2R) were the first to be associated with FGD [6]
Two siblings initially suspected as having FGD, in whom MC2R and MC2R receptor accessory protein (MRAP) sequences were normal, were compound heterozygote carriers of two novel mutations in the StAR gene

Summary

Introduction

Mutations in the StAR gene were first described in patients with classic congenital lipoid adrenal hyperplasia (CLAH) in which both the adrenals and the gonads seemed to completely lack steroidogenesis [1]. Patients described as having the recently described non-classic form of lipoid adrenal hyperplasia (NCLAH) presented with adrenal insufficiency in early infancy or later and, while manifesting with hypocortisolism, had inconsistent signs of mineralocorticoid deficiency [3,4,5], resembling the clinical profile of familial glucocorticoid deficiency (FGD). FGD has been described as a syndrome secondary to ACTH resistance, and inactivating mutations in the gene encoding melanocortin type 2 receptor (MC2R) were the first to be associated with FGD [6]. A second genetic cause of FGD was identified in 15– 20% of patients resulting from defects in the MC2R receptor accessory protein (MRAP) (FGD type 2) [7,8].

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