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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2004-1323
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 2 835-840
Copyright © 2005 by The Endocrine Society

A Genetic Isolate of Congenital Lipoid Adrenal Hyperplasia with Atypical Clinical Findings

Xin Chen, Bo Y. Baker, Mohammad A. Abduljabbar and Walter L. Miller

Department of Pediatrics and Metabolic Research Unit (X.C., B.Y.B., W.L.M.), University of California, San Francisco, California 94143-0978; and Pediatric Service Division, Saudi Aramco Hospital (M.A.A.), 31311 Dhahran, Saudi Arabia

Address all correspondence and requests for reprints to: Prof. Walter L. Miller, Department of Pediatrics, Building MR-IV, Room 205, University of California, San Francisco, California 94143-0978. E-mail: wlmlab{at}itsa.ucsf.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 References
 
Congenital lipoid adrenal hyperplasia (lipoid CAH) is the most severe form of CAH, eventually destroying all adrenal and gonadal steroidogenesis. Lipoid CAH is caused by mutations in the steroidogenic acute regulatory protein (StAR), which facilitates the entry of cholesterol into mitochondria to initiate steroidogenesis. Patients with lipoid CAH typically present with a salt-losing crisis in the first 2 months of life, although presentation as late as 10 months with partial retention of StAR activity has been reported. We describe eight patients from six Saudi Arabian families who were first diagnosed at 1–14 months of age (median, 4–7 months; mean, 7 months). Five patients were 46,XY, and three were 46,XX. At presentation, all had hyponatremia, hyperkalemia, elevated ACTH, and low cortisol. Pregnenolone, progesterone, 17-hydroxypregnenolone, 17-hydroxyprogesterone, testosterone, androstenedione, and dehydroepiandrosterone sulfate were all low in those patients in whom it was measured. DNA sequencing showed that one patient was homozygous for the StAR mutation M144R, and the other seven, from five apparently unrelated families, were homozygous for the StAR mutation R182H. Each mutation was recreated in a human StAR cDNA expression vector and found to be wholly inactive in a standard assay of COS-1 cells cotransfected with the cholesterol side-chain cleavage enzyme system. Thus, the loss of all assayable activity in vitro correlated poorly with the later onset of clinical symptoms in these patients. Lipoid CAH may present much later in life than previously thought.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 References
 
CONGENITAL LIPOID ADRENAL hyperplasia (lipoid CAH) is the most severe form of CAH, in which all steroidogenesis in the adrenals and gonads is impaired. The resulting fetal sex steroid deficiency results in all affected individuals having phenotypically female external genitalia regardless of their karyotypes, and the resulting mineralocorticoid and glucocorticoid deficiency results in hyponatremia, hyperkalemia, acidosis and shock, and is fatal if not treated, although early treatment is compatible with long-term survival (1). Because patients are unable to produce pregnenolone (2), and because affected tissue is unable to convert cholesterol to pregnenolone in vitro (3, 4), it was long thought that these patients had a defect in the cholesterol side-chain cleavage enzyme system; however, analysis of the three components of this system, P450scc, ferredoxin, and ferredoxin reductase, was normal (5). The discovery of the steroidogenic acute regulatory protein (StAR) (6) quickly led to the discovery of StAR mutations in human lipoid CAH (7). Studies of StAR activity in transfected cell systems (7, 8) and clinical analysis of a large series of 21 patients led to the formulation of the two-hit model of lipoid CAH, which explained its clinical features (9). This model distinguishes loss of the acute steroidogenic response secondary to StAR mutations (the first hit) from loss of StAR-independent steroidogenesis as a consequence of accumulation of cellular cholesterol and its esters (the second hit). This model has been confirmed both by clinical observations (10, 11, 12) and by studies with StAR-knockout mice (13, 14).

To date, the StAR mutations in at least 70 patients with lipoid CAH have been characterized (7, 9, 10, 11, 12, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27). The overwhelmingly most common mutation is Q258X, which is found in about 70% of affected alleles from Japan and Korea (7, 9, 11, 12, 16, 17, 18, 19, 20, 21, 23) and accounts for about half of all reported cases. No other genetic isolate of StAR mutations has been demonstrated unambiguously. The mutation R182L has also been reported in several Palestinian patients (9), but this may not be due to a classic genetic founder effect, because some, but not all, of these alleles also carried a frameshift mutation (del 2T593) (9), and R182L has also been described in a Japanese patient (24). We now report a genetic isolate of the mutation R182H in eastern Saudi Arabia and report very long survival before initiation of treatment.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
References
 
Case reports

All patients were of native Saudi Arabian descent. They were evaluated by one of us (M.A.A.), and the families gave informed consent for these studies. All patients had generalized hyperpigmentation and had signs of poor growth, recent weight loss, and dehydration at the time of clinical presentation.

Patient 1 is notable because she had bilateral talipes equinovarus, for which she was placed in a cast as a newborn and followed in the orthopedic clinic. No difficulties were noted during this course or during pediatric visits for routine immunizations. At age 6 months she had an episode of apparent gastroenteritis with mildly abnormal electrolytes (sodium, 127 mEq/liter; potassium, 6.1 mEq/liter; chloride, 97 mEq/liter; CO2, 17 mEq/liter), but she responded well to iv fluids and was not seen again until her scheduled cast removal at 7 months, at which time she had lost 2 kg from her admission at 6 months, and her electrolyte levels were as listed in Table 1Go. The parents of patient 1 are cousins. The father’s brother is also married to the mother’s sister, and that couple has an apparently affected 15-yr-old daughter, who was not available for study.


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  		TABLE 1. Clinical data

 
Patient 2A was an apparently healthy infant for the first several months of life, but then her mother noted that she became lethargic when she experienced routine upper respiratory infections. She was seen by several physicians, who found nothing abnormal. At 1 yr of age the parents noted hair loss and hyperpigmentation. At 14 months she was admitted elsewhere for gastroenteritis and dehydration, at which time she had the electrolyte values listed in Table 1Go and was transferred for additional care and evaluation.

Patient 2B had an adrenal crisis and was diagnosed as having Addison’s disease at 1 yr of age, was treated with glucocorticoids and mineralocorticoids, and underwent spontaneous menarche at 14 yr. She was diagnosed with lipoid CAH at age 17 yr after her sister, patient 2A, was diagnosed. At age 18 yr menses stopped, and treatment with oral contraceptives was begun to suppress gonadotropins and reduce the risk of developing ovarian cysts and ovarian torsion (10).

Patient 3A was small at birth, but did well until about 10 wk of age, when she became less vigorous when feeding. At 3 months she presented with dehydration and shock, with the values shown in Table 1Go, and was treated with glucocorticoids and 9{alpha}-fluorocortisol.

Patient 3B was well until 8 months of age, when she began to have recurrent episodes of vomiting and dehydration, which were treated with iv fluids on several occasions until 13 months, when she presented with an episode of shock (Table 1Go). The family had also noted progressive darkening of the skin. She was treated with glucocorticoids and 9{alpha}-fluorocortisol for Addison’s disease and was first seen by M.A.A. at age 10 yr, at which time her height was at the 50th percentile. She was not hyperpigmented, and the physical examination was unremarkable, except for inguinal masses. The parents in families 2 and 3 are first cousins; furthermore, the mother in family 2 is the first cousin of the father in family 3, and the father in family 2 is the brother of the mother in family 3.

Patient 4 had mediocre Apgar scores of 6 and 7, was hypotonic, fed poorly, and developed tachypnea and mild respiratory distress, but did not require intubation. She remained in the newborn nursery, and at age 2 wk progressive hyperpigmentation was noted, and her serum sodium was 133 mEq/liter. At 1 month of age she was seen by M.A.A., and the diagnosis was made on the basis of the data presented in Table 1Go.

Patient 5 was reportedly the product of a 34-wk gestation, but she had normal birth weight and Apgar scores and was discharged home on the second day of life. She was apparently well until 3 months of age, when her mother noted poor feeding and lethargy. She was admitted and diagnosed by the data presented in Table 1Go. The parents are first cousins, but originate from a different part of Saudi Arabia (the northern or Al Hudud Ash Shamaliyah province), whereas all the other families are from the eastern (Ash Sharqiyah) province.

Patient 6 was apparently well until 4 months of age, when she was admitted elsewhere for poor feeding, vomiting, and dehydration. Her electrolytes were apparently abnormal, and she was treated with unknown steroids for Addison’s disease. At 11 yr of age she was admitted for shock, with tachycardia, an unmeasurable blood pressure, and the values shown in Table 1Go. Her mother said she had stopped taking her medicines a few weeks earlier. She recovered quickly with iv fluids and hydrocortisone. Her height was at the 75th percentile, but the physical examination was unremarkable, and there were no inguinal masses.

DNA sequencing analysis Blood samples in EDTA were shipped to San Francisco by express courier, and DNA was prepared as previously described (10). The oligonucleotide sequences used in DNA amplification reactions (for exons 1–4) were previously described (9). For exons 5–7, the following oligonucleotide sequences are used: exon 5: Ex5S 5'-GCCCAGTGTGAATGCTGTAT-3'; and Ex5AS, 5'-GCCCAGTGTGAATGCTGTAT-3'; exon 6: Ex6S, 5'-GTACCGTAGAAACGTG TTATC-3'; and Ex6AS, 5'-GCCTGTGATTCTATCAGAATAG-3'; and exon 7: Ex7S, 5'-CCTGGCAGCCTGTTTGTGATAG-3'; and Ex7AS, 5'-CCTCATGTCATAGCTAATCA GTG-3'. PCR products were purified through QIAquick PCR purification columns (Qiagen, Valencia, CA) and were sequenced directly in an automated ABI PRISM 3700 sequencer (PerkinElmer Corp., Foster City, CA). The R182H mutation from seven patients and their parents was also confirmed by digesting the PCR products of exon 5 (primer 5S and 5AS) (9, 10, 24) with restriction endonuclease Tsp45I (New England Biolabs, Inc., Beverly, MA) as previously described (9).

Cell transfection and steroid measurement The mutations M144R and R182H were introduced into a previously described wild-type human StAR cDNA expression vector (28), by site-directed mutagenesis. The resulting mutant plasmids were sequenced to ensure that no adventitious mutations had been introduced during the constructions. COS-1 cells were transfected by the calcium phosphate method with the F2 plasmid expressing the cholesterol side-chain cleavage system (29) and empty vector, wild-type StAR, or mutant StAR constructs. The production of pregnenolone was measured by RIA using reagents from MP Biomedicals Corp. (Irvine, CA).

Structural modeling Automated homology modeling of N-62 StAR was performed with the Swiss-Model program (http://expasy.ch/spdbv/) using N-218 MLN64 (PDB ID, 1EM2) as template. Energy minimization was carried out using the Amber 7 program (http://amber.scripps.edu) at the Computer Graphics Laboratory of University of California-San Francisco. The resulting model was checked using the program WHAT IF (http://swift.cmbi.kun.nl/WIWWWI/) for geometric quality.

Results

Hormonal data The essential clinical and hormonal data from all patients are shown in Table 1Go. With the exception of patient 4, all were healthy infants who grew well for the first few months of life. Patients 1, 2A, 2B, and 3B are remarkable in surviving from 7–14 months of age without hormonal replacement therapy. Except for this late age of onset of clinical symptoms, the clinical and hormonal findings in these patients are wholly typical of lipoid CAH. All patients presented with a typical salt-losing crisis, evidenced by dehydration, weight loss, poor feeding, hyponatremia, and hyperkalemia. Hypoglycemia (glucose, <70 mg/dl) was seen in five of the patients. All had profoundly elevated ACTH values and very low cortisol values. In each instance where they were measured, all other steroids were very low. Five of the eight patients were 46,XY, and four of these had palpable inguinal masses. The five 46,XY patients underwent surgical exploration, and histologically proven testes were removed in all cases.

Genetic analysis All coding regions of the StAR gene were sequenced from all the patients and their parents. Patient 5 was homozygous for the mutation T to G at position 431 of the human StAR open reading frame (8) (GenBank accession no. NM_000349), resulting in the missense mutation M144R; both parents were heterozygous (Fig. 1Go). The other seven patients were all homozygous for the mutation G to A at base position 545 in StAR open reading frame, resulting in the missense mutation R182H (Fig. 1Go). All available parental samples were heterozygous.



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  		FIG. 1. DNA sequencing. The region containing the nucleotide changes 431 T->G causing the M144R mutation and 545 G->A causing the R182H mutation are shown for the normal (wild-type) sequence, a representative homozygously affected patient, and a representative heterozygously affected parent. Note the sequence ambiguity, designated by N where the parental sequence has both wild-type and mutant bases.

 
Restriction fragment length polymorphism studies The 545 G->A nucleotide causing the R182H missense mutation changes the wild-type sequence GTGAC, which can be cleaved by the restriction endonuclease Tsp45I, to the sequence ATGAC, which cannot be cleaved. PCR amplification of exon 5 yields a 451-bp product, which is hence cleaved to 266- and 185-bp products by Tsp45I. Digestion of the exon 5 PCR product from an unaffected individual yields the expected fragments. The PCR product from each patient carrying the R182H mutation is undigestible, and the PCR products from the obligately heterozygous parents yield the undigested (mutant) 451-bp product and the digested (wild-type) 266- and 185-bp products (Fig. 2Go).



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  		FIG. 2. Restriction fragment length polymorphism analysis. Exon 5 of the StAR gene was amplified from the seven patients and 10 parents in the five families carrying the R182H mutation identified by sequencing. Each sample was digested with Tsp45I. The lane designated S contains size markers, and the lane designated N contains exon 5 from an unaffected individual, also digested with Tsp45I. None of the patient samples was digested, whereas all of the parental samples showed the 451-bp band representing the undigested mutant allele and the 266- and 185-bp bands representing the normal allele.

 
Functional studies The M144R and R182H mutations were recreated in a human StAR cDNA expression vector. These mutants, the wild-type StAR, and the empty vector were assayed for activity by transfecting each into COS-1 cells together with the F2 vector expressing a fusion protein (H2N-P450scc-ferredoxin reductase-ferredoxin-COOH) of the human cholesterol side-chain cleavage system (29). In this assay, steroidogenesis is measured as the production of pregnenolone from cholesterol that is either endogenous to the cells or is available from the serum in the culture medium. In the absence of StAR, the F2 enzyme exhibits a low level of StAR-independent steroidogenesis (7, 9). The maximum steroidogenic capacity of the F2 enzyme is measured by adding 22R-hydroxycholesterol to the medium at 5 µg/ml (14 µM; the Km of F2 is 2.85 µM) (29). The results (Fig. 3Go) show that the M144R and R182H mutants have no more activity than the empty vector. The competence of the F2 enzyme in these cells is shown by their robust steroidogenesis when given 22R-hydroxycholesterol. By contrast, wild-type StAR induces a dramatic increase in steroidogenesis. Thus, both mutants found in our patients are devoid of StAR activity despite the ability of some of the patients to survive without treatment for many months.



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  		FIG. 3. Pregnenolone production. COS-1 cells were cotransfected with the vector expressing the F2 fusion of the cholesterol side-chain cleavage enzyme system and an empty StAR vector or vectors for wild-type StAR or the R182H or M144R mutants. Cells expressing F2 make 35.6 ± 2.9 ng pregnenolone/ml culture medium when 22R-hydroxycholesterol is provided, but only 2.5 ± 0.5 ng/ml when no 22R-hydroxycholesterol is provided (vector control) (P < 0.001). Wild-type StAR increases pregnenolone production to 11.3 ± 1.2 ng/ml (P < 0.01 compared with vector control), but the R182H and M144R StAR mutants elicit no more pregnenolone than the empty vector (P > 0.4 for either mutant compared with vector control). Data are the mean ± SEM from three independent transfection experiments, each performed in triplicate.

 
Discussion

StAR fosters the movement of cholesterol from the outer mitochondrial membrane (OMM) to the inner mitochondrial membrane (IMM), where it is converted to pregnenolone by P450scc. The crystal structures of the closely related proteins N-216 MLN64 (30) and Star D4 (31) as well as the molecular modeling of hamster StAR (32) indicate that StAR has a helix-grip fold with a hydrophobic pocket that can bind a single molecule of cholesterol (Fig. 4AGo). This structure was initially interpreted to suggest that StAR acts as a cholesterol transfer protein in the mitochondrial intramembranous space, taking cholesterol from the OMM and inserting it into the IMM (30). However, previous experiments indicated that StAR lacking a mitochondrial leader peptide (N-62 StAR) remains confined to the cytoplasm and is fully active (33), and experiments immobilizing StAR on the OMM or the IMM or confining it to the intramembranous space established that StAR acts exclusively on the OMM, and that its level of activity is proportionate to the time it remains on the OMM (28). Although crystallography of MLN64 and modeling of StAR indicate that StAR can bind one molecule of cholesterol, it also indicates that there is insufficient space for a molecule of cholesterol to enter or exit the cholesterol binding pocket (30). This indicates that StAR must undergo conformational changes during the course of its action. Spectroscopic analyses show that StAR undergoes a pH-dependent transition to a partially folded molten globule, both in solution (34) and in association with membranes (35), and liposome protection studies indicate that the carboxy-terminal {alpha}-helix interacts with the OMM (41). Thus, the interaction of StAR with the acidic head groups of the phospholipids on the OMM probably induces a conformational change to a molten globule, permitting association with cholesterol.



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  		FIG. 4. Views of the StAR molecule created with the WebLab viewer. The structure of N-62 StAR is presented as a ribbon diagram. A, View of the whole molecule, featuring prominent {alpha}-helices at the N and C termini. M144 extends into the presumed cholesterol binding pocket above the C-terminal helix, and R182 lies in the {Omega}2 loop. M144 and R182 are shown in ball and stick representations. B, Close-up view of the region where R182 appears to form hydrogen bonds (dotted lines) with G180, located in the same loop, and L247, located in the C-terminal helix.

 
The loss of function of the two mutations we found, M144R and R182H, can be understood from the structural perspective described above (Fig. 4Go). The hydrophobic putative cholesterol binding pocket has a single charged residue, R188, which is predicted to interact with the 3ß-hydroxyl group of the cholesterol. Methionine 144 is only 4.96 Å away, exposed to the inside of the cholesterol binding pocket. Its change to an arginine is predicted to disrupt the salt bridge between R188 and E169, thus disrupting cholesterol binding. Mutation of the hamster StAR residues corresponding to R188 or E169 destroys activity (32). The R182H mutation is especially interesting (Fig. 4BGo). Because this mutation changes a strongly basic residue, arginine (pI 10.76) to a weakly basic residue, histidine (pI 7.58), and because many of the patients who had this mutation had clinically milder, later onset of the symptoms of lipoid CAH, we initially expected this R182H mutant to retain partial activity in vitro. Furthermore, the closely related StAR mutant R182L, in which arginine is changed to a hydrophobic leucine, causes severe lipoid CAH (9), and spectroscopic analysis shows that this mutated protein is grossly misfolded (36). However, our functional studies showed that R182H was devoid of activity. This apparent paradox is explained by inspection of the structure. R182 lies at the beginning of a ß-sheet, forming main chain interactions with the adjacent ß-strand. Molecular modeling and computer graphic analysis show that R182 normally forms two hydrogen bonds with L247 and one hydrogen bond with G180 (Fig. 4Go). However, the R182H mutant cannot form these bonds. The lack of these hydrogen bonds would increase the flexibility of the {Omega} loop region, disrupting formation of the cholesterol binding pocket.

The patients described in this report had substantial variation in the severity of their disease and age of onset of symptoms (Table 1Go). Among the seven patients who carried the same R182H mutation, the onset of symptoms ranged from 1 month (patient 4) to 14 months (patient 2A). This is a most surprising finding for which there is no clear explanation. The latest onset of clinical symptoms previously reported in lipoid CAH is 10 months, in association with a mutation (M225T) that retained substantial activity in vitro (17). A possibility that merits investigation is whether some of these individuals express higher levels of other StAR-like molecules, such as the StAR-like domain of MLN64 (37, 38) or the cytoplasmic StAR homologs Star D4–8 (39), which might be able to replace some of the lost StAR activity.

This report identifies a genetic isolate of the StAR R182H mutation in eastern Saudi Arabia. A previous report described the same R182H mutation in a patient from nearby Qatar, but the in vitro activity of the R182H mutation was not determined (25). In that case, onset of clinical symptoms and laboratory evidence of salt loss were noted at 3 wk of age. Thus, that report and this one show a dramatic spectrum of clinical presentations in the same ethnic group with the same mutation in the same part of the world. This high incidence of R182H suggests that physicians caring for patients from the eastern Arabian peninsula should consider this diagnosis in sick infants and may wish to consider its prenatal diagnosis in appropriately selected families. Prenatal diagnosis is easily accomplished by PCR of DNA from fetal amniocytes, followed by cleavage with the restriction enzyme Tsp45I (9). This, however, will not distinguish the R182H mutation from the R182L mutation previously described in Palestinian Arabs (9). Alternatively, prenatal diagnosis may be possible by examination of maternal estriol and measurement of amniotic fluid steroids (40), as described before the role of StAR in lipoid CAH was known.


   Footnotes
 
First Published Online November 16, 2004

Abbreviations: lipoid CAH, Congenital lipoid adrenal hyperplasia; IMM, inner mitochondrial membrane; OMM, outer mitochondrial membrane; StAR, steroidogenic acute regulatory protein.

This work was supported by NIH grant DK37922 to W.L.M.

Received July 8, 2004.

Accepted November 4, 2004.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 References
 

  1. Hauffa BP, Miller WL, Grumbach MM, Conte FA, Kaplan SL 1985 Congenital adrenal hyperplasia due to deficient cholesterol side-chain cleavage activity (20,22-desmolase) in a patient treated for 18 years. Clin Endocrinol (Oxf) 23:481–493[Medline]
  2. Camacho AM, Kowarski A, Migeon CJ, Brough AJ 1968 Congenital adrenal hyperplasia due to a deficiency of one of the enzymes involved in the biosynthesis of pregnenolone. J Clin Endocrinol Metab 28:153–161[Abstract/Free Full Text]
  3. Degenhart HJ, Visser HK, Boon H, O’Doherty NJ 1972 Evidence for deficient 20-cholesterol-hydroxylase activity in adrenal tissue of a patient with lipoid adrenal hyperplasia. Acta Endocrinol (Copenh) 71:512–518[Abstract/Free Full Text]
  4. Koizumi S, Kyoya S, Miyawaki TM, Kidani H, Funabashi T 1977 Cholesterol side-chain cleavage enzyme activity and cytochrome P-450 content in adrenal mitochondria of a patient with congenital lipoid adrenal hyperplasia (Prader disease). Clin Chim Acta 77:301–306[CrossRef][Medline]
  5. Lin D, Gitelman SE, Saenger P, Miller WL 1991 Normal genes for the cholesterol side chain cleavage enzyme, P450scc, in congenital lipoid adrenal hyperplasia. J Clin Invest 88:1955–1962
  6. Clark BJ, Wells J, King SR, Stocco DM 1994 The purification, cloning, and expression of a novel luteinizing hormone-induced mitochondrial protein in MA-10 mouse Leydig tumor cells. Characterization of the steroidogenic acute regulatory protein (StAR). J Biol Chem 269:28314–28322[Abstract/Free Full Text]
  7. Lin D, Sugawara T, Strauss III JF, Clark BJ, Stocco DM, Saenger P, Rogol A, Miller WL 1995 Role of steroidogenic acute regulatory protein in adrenal and gonadal steroidogenesis. Science 267:1828–1831[Abstract/Free Full Text]
  8. Sugawara T, Holt JA, Driscoll D, Strauss III JF, Lin D, Miller WL, Patterson D, Clancy KP, Hart IM, Clark BJ, Stocco DM 1995 Human steroidogenic acute regulatory protein: functional activity in COS-1 cells, tissue-specific expression, and mapping of the structural gene to 8p11.2 and a pseudogene to chromosome 13. Proc Natl Acad Sci USA 92:4778–4782[Abstract/Free Full Text]
  9. Bose HS, Sugawara T, Strauss III JF, Miller WL 1996 The pathophysiology and genetics of congenital lipoid adrenal hyperplasia. N Engl J Med 335:1870–1878[Abstract/Free Full Text]
  10. Bose HS, Pescovitz OH, Miller WL 1997 Spontaneous feminization in a 46,XX female patient with congenital lipoid adrenal hyperplasia due to a homozygous frameshift mutation in the steroidogenic acute regulatory protein. J Clin Endocrinol Metab 82:1511–1515[Abstract/Free Full Text]
  11. Fujieda K, Tajima T, Nakae J, Sageshima S, Tachibana K, Suwa S, Sugawara T, Strauss III JF 1997 Spontaneous puberty in 46,XX subjects with congenital lipoid adrenal hyperplasia. Ovarian steroidogenesis is spared to some extent despite inactivating mutations in the steroidogenic acute regulatory protein (StAR) gene. J Clin Invest 99:1265–1271[Medline]
  12. Shima M, Tanae A, Miki K, Katsumata N, Matsumoto S, Nakajima S, Harada T, Shinagawa T, Tanaka T, Okada S 2000 Mechanism for the development of ovarian cysts in patients with congenital lipoid adrenal hyperplasia. Eur J Endocrinol 142:274–279[Abstract]
  13. Caron KM, Soo SC, Wetsel WC, Stocco DM, Clark BJ, Parker KL 1997 Targeted disruption of the mouse gene encoding steroidogenic acute regulatory protein provides insights into congenital lipoid adrenal hyperplasia. Proc Natl Acad Sci USA 94:11540–11545[Abstract/Free Full Text]
  14. Hasegawa T, Zhao L, Caron KM, Majdic G, Suzuki T, Shizawa S, Sasano H, Parker KL 2000 Developmental roles of the steroidogenic acute regulatory protein (StAR) as revealed by StAR knockout mice. Mol Endocrinol 14:1462–1471[Abstract/Free Full Text]
  15. Tee MK, Lin D, Sugawara T, Holt JA, Guiguen Y, Buckingham B, Strauss III JF, Miller WL 1995 T->A transversion 11 bp from a splice acceptor site in the human gene for steroidogenic acute regulatory protein causes congenital lipoid adrenal hyperplasia. Hum Mol Genet 4:2299–2305[Abstract/Free Full Text]
  16. Okuyama E, Nishi N, Onishi S, Itoh S, Ishii Y, Miyanaka H, Fujita K, Ichikawa Y 1997 A novel splicing junction mutation in the gene for the steroidogenic acute regulatory protein causes congenital lipoid adrenal hyperplasia. J Clin Endocrinol Metab 82:2337–2342[Abstract/Free Full Text]
  17. Nakae J, Tajima T, Sugawara T, Arakane F, Hanaki K, Hotsubo T, Igarashi N, Igarashi Y, Ishii T, Koda N, Kondo T, Kohno H, Nakagawa Y, Tachibana K, Takeshima Y, Tsubouchi K, Strauss III JF, Fujieda K 1997 Analysis of the steroidogenic acute regulatory protein (StAR) gene in Japanese patients with congenital lipoid adrenal hyperplasia. Hum Mol Genet 6:571–576[Abstract/Free Full Text]
  18. Katsumata N, Tanae A, Shinagawa T, Nagashima-Miyokawa A, Shimizu M, Yasunaga T, Tanaka T, Hibi I 1997 Homozygous Q258X mutation in the steroidogenic acute regulatory gene in a Japanese patient with congenital lipoid adrenal hyperplasia. Endocr J 44:441–446[Medline]
  19. Katsumata N, Tanae A, Shinagawa T, Nagashima-Miyokawa A, Shimizu M, Yasunaga T, Tanaka T, Hibi I 1998 A novel frameshift mutation 840delA and a novel polymorphism D203A in the steroidogenic acute regulatory protein gene in a Japanese patient with congenital lipoid adrenal hyperplasia. Mutations in brief. Hum Mutat 11:331[Medline]
  20. Yoo HW, Kim GH 1998 Molecular and clinical characterization of Korean patients with congenital lipoid adrenal hyperplasia. J Pediatr Endocrinol Metab 11:707–711[Medline]
  21. Katsumata N, Kawada Y, Yamamoto Y, Noda M, Nimura A, Horikawa R, Tanaka T 1999 A novel compound heterozygous mutation in the steroidogenic acute regulatory protein gene in a patient with congenital lipoid adrenal hyperplasia. J Clin Endocrinol Metab 84:3983–3987[Abstract/Free Full Text]
  22. Korsch E, Peter M, Hiort O, Sippell WG, Ure BM, Hauffa BP, Bergmann M 1999 Gonadal histology with testicular carcinoma in situin a 15-year-old 46,XY female patient with a premature termination in the steroidogenic acute regulatory protein causing congenital lipoid adrenal hyperplasia. J Clin Endocrinol Metab 84:1628–1632[Abstract/Free Full Text]
  23. Nakarai T, Saikawa Y, Niida Y, Kanegane C, Honke K, Koizumi S 1999 Spontaneous feminization in a female patient with congenital adrenal lipoid hyperplasia due to a homozygous Q258X mutation in the steroidogenic acute regulatory protein gene. Pediatr Int 41:682–684[Medline]
  24. Bose HS, Sato S, Aisenberg J, Shalev SA, Matsuo N, Miller WL 2000 Mutations in the steroidogenic acute regulatory protein (StAR) in six patients with congenital lipoid adrenal hyperplasia. J Clin Endocrinol Metab 85:3636–3639[Abstract/Free Full Text]
  25. Achermann JC, Meeks JJ, Jeffs B, Das U, Clayton PE, Brook CG, Jameson JL 2001 Molecular and structural analysis of two novel StAR mutations in patients with lipoid congenital adrenal hyperplasia. Mol Genet Metab 73:354–357[CrossRef][Medline]
  26. Gonzalez AA, Reyes ML, Carvajal CA, Tobar JA, Mosso LM, Baquedano P, Solar A, Venegas A, Fardella CE 2004 Congenital lipoid adrenal hyperplasia caused by a novel splicing mutation in the gene for the steroidogenic acute regulatory protein. J Clin Endocrinol Metab 89:946–951[Abstract/Free Full Text]
  27. Gassner HL, Toppari J, Gonzales SQ, Miller WL 2004 Near-miss apparent SIDS from adrenal crisis. J Pediatr 145:178–183[CrossRef][Medline]
  28. Bose H, Lingappa VR, Miller WL 2002 Rapid regulation of steroidogenesis by mitochondrial protein import. Nature 417:87–91[CrossRef][Medline]
  29. Harikrishna JA, Black SM, Szklarz GD, Miller WL 1993 Construction and function of fusion enzymes of the human cytochrome P450scc system. DNA Cell Biol 12:371–379[Medline]
  30. Tsujishita Y, Hurley JH 2000 Structure and lipid transport mechanism of a StAR-related domain. Nat Struct Biol 7:408–414[CrossRef][Medline]
  31. Romanowski MJ, Soccio RE, Breslow JL, Burley SK 2002 Crystal structure of the Mus musculus cholesterol-regulated START protein 4 (StarD4) containing a StAR-related lipid transfer domain. Proc Natl Acad Sci USA 99:6949–6954[Abstract/Free Full Text]
  32. Mathieu AP, Fleury A, Ducharme L, Lavigne P, LeHoux JG 2002 Insights into steroidogenic acute regulatory protein (StAR)-dependent cholesterol transfer in mitochondria: evidence from molecular modeling and structure-based thermodynamics supporting the existence of partially unfolded states of StAR. J Mol Endocrinol 29:327–345[Abstract]
  33. Arakane F, Sugawara T, Nishino H, Liu Z, Holt JA, Pain D, Stocco DM, Miller WL, Strauss III JF 1996 Steroidogenic acute regulatory protein (StAR) retains activity in the absence of its mitochondrial import sequence: implications for the mechanism of StAR action. Proc Natl Acad Sci USA 93:13731–13736[Abstract/Free Full Text]
  34. Bose HS, Whittal RM, Baldwin MA, Miller WL 1999 The active form of the steroidogenic acute regulatory protein, StAR, appears to be a molten globule. Proc Natl Acad Sci USA 96:7250–7255[Abstract/Free Full Text]
  35. Christensen K, Bose HS, Harris FM, Miller WL, Bell JD 2001 Binding of steroidogenic acute regulatory protein to synthetic membranes suggests an active molten globule. J Biol Chem 276:17044–17051[Abstract/Free Full Text]
  36. Bose HS, Baldwin MA, Miller WL 1998 Incorrect folding of steroidogenic acute regulatory protein (StAR) in congenital lipoid adrenal hyperplasia. Biochemistry 37:9768–9775[CrossRef][Medline]
  37. Watari H, Arakane F, Moog-Lutz C, Kallen CB, Tomasetto C, Gerton GL, Rio MC, Baker ME, Strauss III JF 1997 MLN64 contains a domain with homology to the steroidogenic acute regulatory protein (StAR) that stimulates steroidogenesis. Proc Natl Acad Sci USA 94:8462–8467[Abstract/Free Full Text]
  38. Bose HS, Whittal RM, Huang MC, Baldwin MA, Miller WL 2000 N-218 MLN64, a protein with StAR-like steroidogenic activity, is folded and cleaved similarly to StAR. Biochemistry 39:11722–11731[CrossRef][Medline]
  39. Soccio RE, Breslow JL 2003 StAR-related lipid transfer (START) proteins: mediators of intracellular lipid metabolism. J Biol Chem 278:22183–22186[Free Full Text]
  40. Saenger P, Klonari Z, Black SM, Compagnone N, Mellon SH, Fleischer A, Abrams CAL, Shackelton CHL, Miller WL 1995 Prenatal diagnosis of congenital lipoid adrenal hyperplasia. J Clin Endocrinol Metab 80:200–205[Abstract]
  41. Yaworski DC, Baker BY, Bose HS, Jensen LB, Bell JD, Baldwin MA, Miller WL 2005 pH-dependent interactions of the carboxy-terminal helix of steroid-ogenic acute regulatory protein with synthetic membranes. J Biol Chem 280:2045–2054[Abstract/Free Full Text]



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