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Clinical, Genetic, and Functional Characterization of Four Patients Carrying Partial Loss-of-Function Mutations in the Steroidogenic Acute Regulatory Protein (StAR)

Sahakitrungruang, T; Soccio, RE; Lang-Muritano, M; Walker, JM; Achermann, JC; Miller, WL; (2010) Clinical, Genetic, and Functional Characterization of Four Patients Carrying Partial Loss-of-Function Mutations in the Steroidogenic Acute Regulatory Protein (StAR). The Journal of Clinical Endocrinology & Metabolism , 95 (7) 3352 - 3359. 10.1210/jc.2010-0437. Green open access

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Abstract

Context: Nonclassic congenital lipoid adrenal hyperplasia (lipoid CAH) is a recently recognized disorder caused by mutations in the steroidogenic acute regulatory protein (StAR) that retain partial function. Affected individuals can present with a phenotype of late onset adrenal insufficiency with only mild or minimally disordered sexual development.Objectives: The aim was to delineate the clinical spectrum of StAR mutations and correlate phenotype with StAR activity.Patients: Four patients had nonclassic/atypical lipoid CAH. Adrenal insufficiency was manifested at birth in two patients and at 11 months and 4 yr in the other two. Three were 46, XY with underdeveloped genitalia.Methods: The StAR gene was sequenced, mutations were recreated in expression vectors, and StAR activity was measured as pregnenolone production in COS-1 cells cotransfected with the cholesterol side-chain cleavage system. StAR mutants were expressed as N-62 StAR in bacteria, and purified proteins were tested for activity with isolated steroidogenic mitochondria and for cholesterol-binding capacity.Results: DNA sequencing identified mutations on all alleles. Missense mutations were R188C, G221D, L260P, and F267S; we also tested R192C described by others. The respective activities of R188C, R192C, G221D, L260P, and F267S were 8.0, 39.4, 2.4, 3.1, and 6.1% of wild-type in transfected cells, and 12.8, 54.8, 6.3, 1.8, and 9.5% with isolated mitochondria. Cholesterol binding capacities of R188C, R192C, G221D, L260P, and F267S were 6.7, 55.3, 10.2, 4.6, and 20.9%. These data are correlated to the three-dimensional structure of StAR.Conclusions: There is a broad clinical spectrum of StAR mutations; StAR activities in vitro correlate well with clinical phenotypes. (J Clin Endocrinol Metab 95: 3352-3359, 2010)

Type: Article
Title: Clinical, Genetic, and Functional Characterization of Four Patients Carrying Partial Loss-of-Function Mutations in the Steroidogenic Acute Regulatory Protein (StAR)
Open access status: An open access version is available from UCL Discovery
DOI: 10.1210/jc.2010-0437
Publisher version: http://dx.doi.org/10.1210/jc.2010-0437
Language: English
Additional information: © 2010 by The Endocrine Society This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/us/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: LIPOID ADRENAL-HYPERPLASIA, CHAIN CLEAVAGE ENZYME, MOLTEN GLOBULE, CHOLESTEROL TRANSPORT, SYNTHETIC MEMBRANES, FEMALE-PATIENT, MECHANISM, P450SCC, IMPORT, BIOSYNTHESIS
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept
URI: https://discovery.ucl.ac.uk/id/eprint/106244
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