Clinical, genetic, and functional characterization of four patients carrying partial loss-of-function mutations in the steroidogenic acute regulatory protein (StAR).
BACKGROUND
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.


OBJECTIVE
The aim was to delineate the clinical spectrum of StAR mutations and correlate phenotype with StAR activity.


METHODS
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.
Sahakitrungruang
Taninee
T
Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, 10330 Bangkok, Thailand. [corrected].
Soccio
Raymond E
RE
Lang-Muritano
Mariarosaria
M
Walker
Joanna M
JM
Achermann
John C
JC
Miller
Walter L
WL
D000293:Adolescent; D000312:Adrenal Hyperplasia, Congenital / Q000235:genetics* / Q000378:metabolism; D000309:Adrenal Insufficiency / Q000235:genetics / Q000378:metabolism; D000328:Adult; D002675:Child, Preschool; D002784:Cholesterol / Q000235:genetics / Q000378:metabolism; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D007223:Infant; D008297:Male; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D000098682:Steroidogenic Acute Regulatory Protein
D010750:Phosphoproteins; D000098682:Steroidogenic Acute Regulatory Protein; D002784:Cholesterol
N Engl J Med. 1996 Dec 19;335(25):1870-8
8948562
Proc Natl Acad Sci U S A. 2002 May 14;99(10):6949-54
12011453
Proc Natl Acad Sci U S A. 1999 Jun 22;96(13):7250-5
10377400
J Clin Endocrinol Metab. 2000 Oct;85(10):3636-9
11061515
Hum Mol Genet. 1995 Dec;4(12):2299-305
8634702
Endocrinology. 1986 Apr;118(4):1296-305
2419119
J Biol Chem. 2008 Apr 4;283(14):8837-45
18250166
J Clin Invest. 1997 Mar 15;99(6):1265-71
9077535
J Clin Endocrinol Metab. 1997 May;82(5):1511-5
9141542
J Biol Chem. 2006 Dec 15;281(50):38879-93
17050526
Nat Struct Biol. 2002 Jul;9(7):507-11
12055623
J Clin Endocrinol Metab. 2009 Oct;94(10):3865-71
19773404
J Biol Chem. 2007 Apr 6;282(14):10223-32
17301050
J Clin Endocrinol Metab. 2005 Sep;90(9):5304-8
15985476
Mol Endocrinol. 2005 Feb;19(2):540-54
15498831
Clin Endocrinol (Oxf). 1985 Nov;23(5):481-93
3841304
Hum Mol Genet. 1997 Apr;6(4):571-6
9097960
Nature. 2002 May 2;417(6884):87-91
11986670
J Biol Chem. 2005 Jan 21;280(3):2045-54
15489236
J Clin Endocrinol Metab. 2010 Mar;95(3):1301-8
20080861
J Clin Endocrinol Metab. 2008 Mar;93(3):696-702
18182448
J Biol Chem. 2005 Dec 16;280(50):41753-60
16234239
Mol Endocrinol. 2007 Mar;21(3):589-601
16973755
J Mol Endocrinol. 1997 Dec;19(3):227-40
9460644
DNA Cell Biol. 1993 Jun;12(5):371-9
8517924
Proc Natl Acad Sci U S A. 1995 May 23;92(11):4778-82
7761400
J Clin Endocrinol Metab. 2006 Dec;91(12):4781-4785
16968793
J Steroid Biochem Mol Biol. 1999 Apr-Jun;69(1-6):131-41
10418987
J Biol Chem. 2001 May 18;276(20):17044-51
11279152
J Mol Endocrinol. 2002 Dec;29(3):327-45
12459035
Biochim Biophys Acta. 2009 Jul;1791(7):646-58
19286473
Science. 1995 Mar 24;267(5205):1828-31
7892608
Biochemistry. 1995 Oct 3;34(39):12506-12
7547998
J Clin Invest. 1991 Dec;88(6):1955-62
1661294
Endocr Rev. 1996 Jun;17(3):221-44
8771357
J Clin Endocrinol Metab. 1997 Jul;82(7):2337-42
9215316
Nat Struct Biol. 2000 May;7(5):408-14
10802740
J Clin Endocrinol Metab. 1999 May;84(5):1628-32
10323391
Proc Natl Acad Sci U S A. 1996 Nov 26;93(24):13731-6
8943003