Unique Dominant Negative Mutation in the N-Terminal Mitochondrial Targeting Sequence of StAR, Causing a Variant Form of Congenital Lipoid Adrenal Hyperplasia

BAQUEDANO M S,; GUERCIO G; MARINO R, .; BERENSZTEIN E; COSTANZO M,; BAILEZ M; VAIANI E ,; MACEIRAS M,; RAMIREZ P, .; CHALER E; RIVAROLA, M; BELGOROSKY A

JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM

ENDOCRINE SOC

Año: 2013 p. 1 - 9

0021-972X

 Unique Dominant Negative Mutation in theN-Terminal Mitochondrial Targeting Sequence ofStAR, Causing a Variant Form of Congenital LipoidAdrenal HyperplasiaMaría Sonia Baquedano,* Gabriela Guercio,* Roxana Marino,Esperanza Berensztein, Mariana Costanzo, Marcela Bailez, Elisa Vaiani,Mercedes Maceiras, Pablo Ramirez, Eduardo Chaler, Marco A. Rivarola,and Alicia BelgoroskyEndocrine Service, Hospital de Pediatria Garrahan, Buenos Aires C1245AAM, ArgentinaContext: Steroid acute regulatory (StAR) protein is a mitochondria-targeted protein that is part ofthe transduceosome complex crucial for transport of cholesterol to mitochondria. Recessive mutationscause classic and nonclassic congenital lipoid adrenal hyperplasia.Objective: The aim of this study was to report the clinical, hormonal, genetic, and functional dataof a novel heterozygous mutation in the StAR gene found in a 46,XY patient with ambiguousgenitalia and neonatal severe steroidogenic deficiency.Patient: Undetectable serum steroids with high ACTH and plasma renin activity but normal acuteGnRH response were found in infancy. After gonadectomy (at 3 yr of age), serum LH and testosteronewere undetectable, whereas FSH was normal but increased slowly afterward. Estrogenreplacement therapy, started at 10.2 yr of age, suppressed gonadotropins (for 2 yr). However, after1 month off estrogens, the patient showed castrated levels. At 11.9 yr old, after fludrocortisonewithdrawal because of hypertension, plasma renin activity and aldosterone remained normal,suggesting mineralocorticoid recovery by a StAR-independent mechanism.Results: We found a de novo heterozygous IVS-2A
G StAR mutation and the reported heterozygousp.G146A SF1 polymorphism with normal CYP11A1, FDXR, FDX1, VDAC1, and TSPO genes. Themutant StAR transcript lacked exon 2, resulting in the in-frame loss of amino acids 22 to 59 in theN-terminal mitochondrial targeting signal. In vitro, the mutant protein exhibited reduced StARactivity in a dominant-negative manner and almost no mitochondria localization.Conclusions:Amisfolded p.G22_L59del StAR might interfere with wild-type StAR activity by blockingthe transduceosome complex, causing an autosomal dominant form of StAR deficiency, explainingthe clinical phenotype. We speculated that estrogen might have modulated mineralocorticoidfunction and pubertal maturation in a human natural model lacking endogenous steroidproduction. (J Clin Endocrinol Metab 98: 0000?0000, 2013)