Unique Dominant Negative Mutation in the N-Terminal Mitochondrial Targeting Sequence of StAR, Causing a Variant Form of Congenital Lipoid Adrenal Hyperplasia
| Autor: | Marco A. Rivarola, Elisa Vaiani, Eduardo Chaler, Alicia Belgorosky, Mariana Costanzo, Esperanza Berensztein, Mercedes Maceiras, Gabriela Guercio, Pablo Ramírez, María Sonia Baquedano, Marcela Bailez, Roxana Marino |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Male
endocrine system medicine.medical_specialty medicine.drug_class Endocrinology Diabetes and Metabolism Fludrocortisone Clinical Biochemistry Disorders of Sex Development Mutation Missense Protein Sorting Signals Biology Dominant-Negative Mutation Polymorphism Single Nucleotide Biochemistry Plasma renin activity chemistry.chemical_compound Endocrinology Internal medicine Chlorocebus aethiops medicine Animals Humans Child Genes Dominant Disorder of Sex Development 46 XY Aldosterone Adrenal Hyperplasia Congenital Cholesterol side-chain cleavage enzyme Biochemistry (medical) Infant Newborn Phosphoproteins Mitochondria Pedigree Protein Structure Tertiary Protein Transport chemistry Estrogen COS Cells Female Gonadotropin medicine.drug Hormone |
| Zdroj: | The Journal of Clinical Endocrinology & Metabolism. 98:E153-E161 |
| ISSN: | 1945-7197 0021-972X |
| Popis: | Steroid acute regulatory (StAR) protein is a mitochondria-targeted protein that is part of the transduceosome complex crucial for transport of cholesterol to mitochondria. Recessive mutations cause classic and nonclassic congenital lipoid adrenal hyperplasia.The aim of this study was to report the clinical, hormonal, genetic, and functional data of a novel heterozygous mutation in the StAR gene found in a 46,XY patient with ambiguous genitalia and neonatal severe steroidogenic deficiency.Undetectable serum steroids with high ACTH and plasma renin activity but normal acute GnRH response were found in infancy. After gonadectomy (at 3 yr of age), serum LH and testosterone were undetectable, whereas FSH was normal but increased slowly afterward. Estrogen replacement therapy, started at 10.2 yr of age, suppressed gonadotropins (for 2 yr). However, after 1 month off estrogens, the patient showed castrated levels. At 11.9 yr old, after fludrocortisone withdrawal because of hypertension, plasma renin activity and aldosterone remained normal, suggesting mineralocorticoid recovery by a StAR-independent mechanism.We found a de novo heterozygous IVS-2AG StAR mutation and the reported heterozygous p.G146A SF1 polymorphism with normal CYP11A1, FDXR, FDX1, VDAC1, and TSPO genes. The mutant StAR transcript lacked exon 2, resulting in the in-frame loss of amino acids 22 to 59 in the N-terminal mitochondrial targeting signal. In vitro, the mutant protein exhibited reduced StAR activity in a dominant-negative manner and almost no mitochondria localization.A misfolded p.G22_L59del StAR might interfere with wild-type StAR activity by blocking the transduceosome complex, causing an autosomal dominant form of StAR deficiency, explaining the clinical phenotype. We speculated that estrogen might have modulated mineralocorticoid function and pubertal maturation in a human natural model lacking endogenous steroid production. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|