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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 10 3636-3639
Copyright © 2000 by The Endocrine Society

Original Studies

Mutations in the Steroidogenic Acute Regulatory Protein (StAR) in Six Patients with Congenital Lipoid Adrenal Hyperplasia1

Himangshu S. Bose2, Seiji Sato, Javier Aisenberg, Stavit A. Shalev, Nobutake Matsuo and Walter L. Miller

Department of Pediatrics and Metabolic Research Unit, University of California (H.S.B., W.L.M.), San Francisco, California 94143-0978; Department of Pediatrics, Keio University Medical School (S.S., N.M.), Tokyo 160, Japan; Hackensack University Medical Center (J.A.), Hackensack, New Jersey 07601; and Ha’Emek Medical Center (S.A.S.), Afula 18101, Israel

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.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Congenital lipoid adrenal hyperplasia (lipoid CAH), the most severe form of CAH, is caused by mutations in the steroidogenic acute regulatory protein (StAR). Lipoid CAH is common among the Japanese, Korean, and Palestinian Arab populations, but is rare elsewhere. We describe six patients with lipoid CAH: four Japanese, one Palestinian, and one Guatemalan Native American. All had classical clinical presentations of normal female external genitalia in both genetic sexes, with severe glucocorticoid and mineralocorticoid deficiency presenting in the first month of life. Quite atypically, one patient had small adrenal glands shown by computed tomographic scanning. The StAR genes were characterized in all six patients. Three of the Japanese patients were compound heterozygotes for the common Japanese mutation Q258X in association with three different novel frameshift mutations; the fourth Japanese patient was homozygous for the mutation R182L, which is common among Palestinian patients but has not been described previously in a Japanese patient. Our Palestinian and Native American patients were each homozygous for novel frameshift mutations. Thus we have found five new frameshift mutations, but no new amino acid replacement (missense) mutations. This would be consistent with the view that only a small number of residues in the StAR protein are crucial for biological activity. The tomographic finding of small adrenals in a patient with genetically proven lipoid CAH due to a StAR mutation suggests a substantially broader spectrum of clinical findings in this disease than has been appreciated previously.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
CONGENITAL LIPOID adrenal hyperplasia (lipoid CAH) is the most severe form of CAH, in which the adrenals and gonads exhibit a severe defect in the conversion of cholesterol to pregnenolone. The hormonal disorder and the levels of the hormonal block were the first investigated by Prader and associates in the mid 1950s, although pathological descriptions of infants dying from lipoid CAH had appeared previously (for review, see Ref. 1). Studies of affected adrenal or testicular tissue or their isolated mitochondria showed an inability to convert cholesterol to pregnenolone; hence, this disorder was thought to lie in the enzyme system that catalyzes this reaction. This reaction, formerly termed 20,22-desmolase, consists of three sequential steps: 20{alpha}-hydroxylation, 22-hydroxylation, and scission of the cholesterol side-chain (2). Studies in the 1970s and 1980s showed that all three of these reactions are catalyzed by a single protein, the cholesterol side-chain cleavage enzyme, which is mitochondrial cytochrome P450scc (for review, see Ref. 3). P450scc and its electron transfer donors, adrenodoxin reductase and adrenodoxin, are found in the mitochondria of the adrenals, gonads, placenta, and brain (4, 5, 6, 7, 8), but patients with lipoid CAH have normal genes for all three enzymes (9, 10, 11). Furthermore, placental biosynthesis of progesterone remains unaffected in the midterm fetus with lipoid CAH, proving that the P450scc system remains unaffected in the patients (12). Thus, the gene that is disrupted in lipoid CAH is expressed in adrenals and gonads, but not in placenta, and affects a step before cholesterol reaches P450scc.

In 1994, Stocco’s laboratory cloned the complementary DNA for a 30-kDa mouse mitochondrial protein that appears to be the rapidly inducible, cyclohexamide-sensitive mediator of the acute steroidogenic response and named it the steroidogenic acute regulatory protein (StAR) (13). Cloning of the human complementary DNA showed that it is expressed in adrenals and gonads, but not in placenta, making it an excellent candidate for the gene affected in lipoid CAH (14). We then showed that StAR was required for the entry of cholesterol, but not of hydroxysterols, into the mitochondria, thus showing that StAR functions by facilitating cholesterol access to P450scc (15), and we found StAR mutations in a wide variety of patients with lipoid CAH (15, 16, 17). This led to the two-hit model of lipoid CAH, in which the presence of low levels of StAR-independent steroidogenesis precede a complete loss of steroidogenesis due to cellular destruction by accumulated lipids (17). This explains the presence of androgen-dependent Wolfian duct remnants in 46,XY fetuses (18) and the delayed onset of mineralocorticoid deficiency in many patients (17). The two-hit model also correctly predicted that affected 46,XX patients would undergo spontaneous puberty (19, 20) and was confirmed by observations in StAR knockout mice (21).

We noted that the StAR mutation Q258X was very common among Japanese and Korean patients with lipoid CAH (15, 17), and this was soon confirmed by others (20, 22, 23). In addition, we found that the mutation R182L was common among Palestinian Arabs (17). Nakae et al. found five Japanese alleles with the mutation 246InsG (22), and three groups found five Japanese alleles carrying A218V (17, 22, 24). All other StAR mutations described to date appear to be "private" mutations, appearing in individual families rather than being widespread in an ethnic group. We now report the mutations in six additional patients, including four Japanese, one Arab, and one Hispanic Native American, with the novel finding of the R182L mutation in a Japanese patient and the identification of five new mutations.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Informed consent was obtained from each family, and blood samples in ethylenediamine tetraacetate were used to prepare genomic DNA as previously described (19). The DNA of the Japanese patients was first amplified with oligonucleotides S4 and AS1 (15) and was cut with EcoRII to screen for the common Q258X mutation, as previously described (17). The oligonucleotide sequences and PCR conditions were previously described (17, 19). PCR products were either cloned or sequenced directly in an automated ABI 377 sequencer (Perkin-Elmer Corp., Foster City, CA).

Case reports

Cases 1–4. Detailed information about cases 1–4 is not available. All were Japanese and presented in infancy with an Addisonian crisis and normal-appearing female genitalia, and were treated with hydrocortisone and fludrocortisone. It is known that case 1 was not the product of a consanguineous marriage. Case 2, which was subsequently found to be 46,XX, had periodic vaginal bleeding beginning in adolescence, but experienced menopause at 24 yr of age.

Case 5. This was the third surviving child of a consanguineous Arab Israeli marriage; twin premature girls and a term male died in infancy, and there were two spontaneous abortions. The mother had low estriol levels throughout pregnancy, but delivered a full-term normal-appearing female infant. At 2 weeks of age she was hospitalized for congenital Addison’s disease with electrolyte abnormalities, low cortisol, androgen, aldosterone, and 17-hydroxyprogesterone levels, and hypotensive shock. PRA was high, but adrenal steroids were minimal after ACTH infusion. Treatment with hydrocortisone and fludrocortisone was effective, but the child has grown poorly.

Case 6. This patient was a full-term normal-appearing female infant born of a consanguineous Guatemalan Amerindian marriage; at 2 months of age she had vomiting, diarrhea, weight loss, hyponatremia, hypoglycemia, and metabolic acidosis while in Guatemala. At 6 months she was hospitalized in the U.S. and required assisted ventilation. PRA was very high, but no cortisol, dehydroepiandrosterone, aldosterone, 17- hydroxypregnenolone, 17-hydroxyprogesterone, or testosterone was detected in response to ACTH, hCG, or GnRH. One examiner thought that there was very mild posterior labial fusion, but no cliteromegaly. Both adrenals were seen on computed tomography of the abdomen, but there was no adrenal enlargement; on ultrasonography the right adrenal measured 0.8 x 0.5 x 1.1 cm, but the left adrenal was not seen. The child was treated successfully with hydrocortisone and fludrocortisone and remained well 3 months later.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Most StAR mutations causing lipoid CAH are found in exons 5–7 of the StAR gene (15, 17, 20, 22). Therefore, we first amplified a 2.1-kb fragment of genomic DNA with the S3 and AS1 primers and sequenced each exon as previously described (15, 16, 17, 19). The genetic data are summarized in Table 1Go. Patient 1 was homozygous for the missense mutation R182 L. This finding from the DNA sequencing was confirmed by restriction endonuclease digestion with Tsp45I, which cleaves the normal sequence, but not the mutant (17). We have previously shown that this mutation is devoid of activity (17) due to profoundly disordered protein folding (25). Digestion with EcoRII showed that patients 2, 3, and 4 are all heterozygous for the Q258X mutation commonly found in Japanese patients (17). This mutation truncates the StAR protein by only 28 amino acids, but eliminates all activity, demonstrating the crucial role of the carboxyl-terminal sequence of StAR (15, 17). Sequencing of cloned DNA for all other exons did not initially reveal mutations; however, because cloning may result in the analysis of only one allele, we directly sequenced the PCR products to ensure that both alleles were examined. This showed that patient 2 carries the mutation deletion of G at nucleotide 189, patient 3 had insertion of A at nucleotide 163, and patient 4 also had insertion of T at nucleotide 643. All mutations were confirmed by performing direct sequencing from three separate PCR reactions. Thus, Japanese patients 2, 3, and 4 were compound heterozygotes for the common Q258X mutation and for three novel mutations. All of the novel mutations caused shifts in the protein reading-frame, which changed the sequence of the biologically essential C-terminus. Patient 5, from a consanguineous Arab Israeli family, was homozygous for a replacement of T for C at nucleotide 703, resulting in the premature stop codon R193X. Patient 6, from a consanguineous Guatemalan Amerindian family, was homozygous for the insertion of an additional A following base 677 in exon 6, causing a frame shift. Thus, one new premature translational termination mutation and four new frameshift mutations were found, but no new missense mutations were found.


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  		Table 1. Genetic data

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The StAR gene mutations in at least 57 patients with lipoid CAH have now been described (15, 16, 17, 19, 20, 22, 23, 24, 26, 27). Because some patients were siblings or were the products of known consanguinity, these 57 patients represent only 99 unique alleles; the mutations in these alleles are summarized in Table 2Go. The only consistent genetic clusters identified to date are the Q258X mutation in the Japanese and Korean populations (15, 17, 20, 22, 23) and R182L among Palestinian Arabs (17). Our present finding of the Palestinian R182L mutation in a Japanese family was surprising and was carefully confirmed in independent samples to eliminate the possibility of a mix-up of samples in the laboratory. As R182L has never been found in any other Japanese patient, we believe it is most likely that patient 1 was the result of a spontaneous mutation and unknown consanguinity, rather than some ancient mixing of these two very distant populations.


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  		Table 2. Known mutations of StAR in lipoid CAH

 
As reviewed previously (1), the StAR missense mutations that cause lipoid CAH are all clustered in exons 5–7, whereas nonsense and frameshift mutations are found throughout the gene. All frameshift mutations described to date have wholly inactivated the StAR gene product, as all of these mutations lie upstream from the crucial carboxyl-terminal 28 amino acids. The location of missense mutations in the carboxyl-terminal 40% of the protein is consistent with this being the functional domain of StAR. Deletion of only 10 carboxyl-terminal amino acids reduces StAR activity by half (28), and deletion of only 28 carboxyl-terminal amino acids deletes all activity (15); by contrast, at least 62 amino-terminal amino acids can be deleted without loss of activity (28). The small number of missense mutations that cause lipoid CAH all lie between amino acids 169 and 275 (of the 285-residue sequence) (1), and these tend to be the residues most highly conserved in the related protein, MLN-64 (29). These missense mutations change the 3-dimensional folding of StAR (25). Biophysical data indicate that residues 63–193 of StAR slow the protein’s transit into the mitochondria, permitting the biologically active carboxyl-terminus to have more interactions with the outer mitochondrial membrane (30). The nature of this interaction remains unclear, but does not appear to require a mitochondrial receptor for StAR, as StAR can transfer cholesterol to several different kinds of intracellular membranes (31).

The diagnosis of lipoid CAH must be distinguished from other combined glucocorticoid and mineralocorticoid deficiencies (32). The distinction between lipoid CAH and 21-hydroxylase deficiency is simple; patients with lipoid CAH have female external genitalia regardless of karyotype and have very low or unmeasurable levels of all steroid hormones (17, 22, 32), whereas patients with 21-hydroxylase deficiency have high concentrations of 21-deoxysteroids, especially 17-hydroxyprogesterone, and affected 46,XX individuals are virilized. However, lipoid CAH can be mistaken for 3ß-hydroxysteroid dehydrogenase deficiency when 17- hydroxypregnenolone (which is grossly elevated in 3ß-hydroxysteroid dehydrogenase deficiency) is not measured (12). The most difficult differential diagnosis probably is between lipoid CAH and congenital adrenal hypoplasia. In the presence of female external genitalia, an XY karyotype strongly suggests lipoid CAH, as in four of our six patients. However, the diagnosis of lipoid CAH in 46,XX patients generally depends on the radiographic demonstration of massively enlarged adrenals, (17, 19, 22, 32), which are not found in adrenal hypoplasia. Thus, the finding of normal sized to small adrenals by computed tomography in our 46,XY Guatemalan Amerindian patient was most surprising. This observation was confirmed by ultrasonography, which showed a 0.8 x 0.5 x 1.1-cm right adrenal and a nonvisualized left adrenal. In the absence of adrenal histology, we can offer no further explanation of these findings. However, as the diagnosis of lipoid CAH was proven by finding a homozygous frameshift mutation, this patient suggests that the clinical spectrum of patients with lipoid CAH is broader than had been appreciated previously. Genetic analysis of the StAR and DAX genes may be needed to establish unambiguous diagnosis.


   Footnotes
 
1 This work was supported by NIH Grants DK-37922, DK-42154, and HD-34449 (to W.L.M.). Back

2 Supported by Pediatric Endocrinology Training Grant DK-07161 (to W.L.M.). Back

Received April 17, 2000.

Revised June 27, 2000.

Accepted June 30, 2000.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Miller WL. 1997 Congenital lipoid adrenal hyperplasia: the human gene knockout of the steroidogenic acute regulatory protein. J Mol Endocrinol. 17:227–240.
  2. Shimizu K, Hayano M, Gut M, Dorfman RI. 1961 The transformation of 20{alpha}-hydroxcholesterol to isocaproic acid and C21 steroids. J Biol Chem. 236:695–699.[Free Full Text]
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  6. Picado-Leonard J, Voutilainen R, Kao L, Chung B, Strauss III JF, Miller WL. 1988 Human adrenodoxin: cloning of three cDNAs and cycloheximide enhancement in JEG-3 cells. J Biol Chem. 263:3240–3244 (corrected 11016).[Abstract/Free Full Text]
  7. Solish SB, Picado-Leonard J, Morel Y, et al. 1988 Human adrenodoxin reductase: two mRNAs encoded by a single gene of chromosome 17cen{Delta}q25 are expressed in steroidogenic tissues. Proc Natl Acad Sci USA. 71:7104–7108.
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  12. Saenger P, Klonari Z, Black SM, et al. 1995 Prenatal diagnosis of congenital lipoid adrenal hyperplasia. J Clin Endocrinol Metab. 80:200–205.[Abstract]
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  27. Korsh E, Peter M, Hiort O, et al. 1999 Gonadal histology with testicular carcinoma in situ in 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]
  28. Arakane F, Sugawara T, Nishino H, et al. 1996 Steroidogenic acute regulatory protein (StAR) retains activity in the absence of its mitochondrial targeting sequence: implications for the mechanism of StAR action. Proc Natl Acad Sci USA. 93:13731–13736.[Abstract/Free Full Text]
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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals