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

被引:55
|
作者
Sahakitrungruang, Taninee [1 ,2 ]
Soccio, Raymond E. [3 ]
Lang-Muritano, Mariarosaria [4 ]
Walker, Joanna M. [5 ]
Achermann, John C. [6 ]
Miller, Walter L. [1 ]
机构
[1] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA
[2] Chulalongkorn Univ, Dept Pediat, Bangkok 10330, Thailand
[3] Hosp Univ Penn, Div Endocrinol Diabet & Metab, Philadelphia, PA 19104 USA
[4] Univ Childrens Hosp, CH-8008 Zurich, Switzerland
[5] Portsmouth Hosp Natl Hlth Serv Trust, Portsmouth PO6 3LY, Hants, England
[6] UCL, Clin & Mol Genet Unit, Dev Endocrinol Res Grp, UCL Inst Child Hlth, London WC1N 1EH, England
来源
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM | 2010年 / 95卷 / 07期
基金
英国惠康基金; 美国国家卫生研究院;
关键词
LIPOID ADRENAL-HYPERPLASIA; CHAIN CLEAVAGE ENZYME; MOLTEN GLOBULE; CHOLESTEROL TRANSPORT; SYNTHETIC MEMBRANES; FEMALE-PATIENT; MECHANISM; P450SCC; IMPORT; BIOSYNTHESIS;
D O I
10.1210/jc.2010-0437
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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)
引用
收藏
页码:3352 / 3359
页数:8
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