Congenital lipoid adrenal hyperplasia: functional characterization of three novel mutations in the STAR gene.
| Autor: | Bens S; Division of Pediatric Endocrinology, Department of Pediatrics, University Hospital Schleswig- Holstein, Schwanenweg 20, D-24105 Kiel, Germany., Mohn A, Yüksel B, Kulle AE, Michalek M, Chiarelli F, Nuri Ozbek M, Leuschner I, Grötzinger J, Holterhus PM, Riepe FG |
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| Jazyk: | angličtina |
| Zdroj: | The Journal of clinical endocrinology and metabolism [J Clin Endocrinol Metab] 2010 Mar; Vol. 95 (3), pp. 1301-8. Date of Electronic Publication: 2010 Jan 15. |
| DOI: | 10.1210/jc.2009-1176 |
| Abstrakt: | Context: The steroidogenic acute regulatory protein (StAR) has been shown to be essential for steroidogenesis by mediating cholesterol transfer into mitochondria. Inactivating StAR mutations cause the typical clinical picture of congenital lipoid adrenal hyperplasia. Objective: The objective of the investigation was to study the functional and structural consequences of three novel StAR mutations (p.N148K in an Italian patient; p.P129fs and p.Q128R in a Turkish patient). Methods and Results: Transient in vitro expression of the mutant proteins together with P450 side-chain cleavage enzyme, adrenodoxin, and adrenodoxin reductase yielded severely diminished cholesterol conversion of the p.N148K mutant, the combined p.P129fs and p.Q128R mutant, and the p.P129fs mutant by itself. The p.Q128R mutant led to a higher cholesterol conversion than the wild-type StAR protein. As derived from three-dimensional protein modeling, the residue N148 is lining the ligand cavity of StAR. A positively charged lysine residue at position 148 disturbs the hydrophobic cluster formed by the alpha4-helix and the sterol binding pocket. The frame shift mutation p.P129fs truncates the StAR protein. Residue p.Q128 is situated at the surface of the molecule and is not part of any functionally characterized region of the protein. Conclusion: The mutations p.N148K and p.P129fs cause adrenal insufficiency in both cases and lead to a disorder of sex development with complete sex reversal in the 46, XY case. The mutation p.Q128R, which is not relevant for the patient's phenotype, is the first reported variant showing a gain of function. We speculate that the substitution of hydrophilic glutamine with basic arginine at the surface of the molecule may accelerate cholesterol transfer. |
| Databáze: | MEDLINE |
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