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Testicular Dysgenesis without Adrenal Insufficiency in a 46,XY Patient with a Heterozygous Inactive Mutation of Steroidogenic Factor-1

Department of Pediatrics, Keio University School of Medicine (T.H., G.S.), Tokyo 160-8582, Japan; Department of Urology, Asoka Hospital (K.F.), Tokyo 135-0002, Japan; Division of Cell Differentiation, National Institute for Basic Biology (K.-I.M.), Okazaki 444-8585, Japan; and Department of Endocrinology and Metabolism, National Research Institute for Child Health and Development (M.F., N.S., N.K., T.O.), Tokyo 154-8567, Japan

Address all correspondence and requests for reprints to: Dr. Tsutomu Ogata, Department of Endocrinology and Metabolism, National Research Institute for Child Health and Development, 3-35-31 Taishido, Setagaya, Tokyo 154-8567, Japan. E-mail: tomogata{at}nch.go.jp.

	Abstract

Top Abstract Introduction Patient and Methods Results Discussion References

 
Steroidogenic factor-1 (SF-1) regulates multiple genes involved in the adrenal and gonadal development and in the biosynthesis of a variety of hormones, including adrenal and gonadal steroids, anti-Mullerian hormone (AMH), and gonadotropins. We identified a novel SF-1 mutation in a 27-yr-old Japanese patient with a 46,XY karyotype. Sequence analysis was performed for all the seven exons of SF-1, revealing a heterozygous single base pair deletion at exon 2 (18delC) that is predicted to cause a frameshift at the sixth codon and resultant termination at the 74th codon. Functional studies showed that the mutation produced no demonstrable protein and had no transcription activity or dominant negative effect. Clinical features included small dysgenetic testes with vasa deferentia and epididymides, absent uterus, blind-ending vagina, clitoromegaly, and psychosexual disturbance. Endocrine studies showed normal adrenal function (cortisol response to ACTH stimulation, 13.425.3 µg/dl) and primary hypogonadism (testosterone response to hCG stimulation, 0.570.76 ng/ml; gonadotropin responses to GnRH stimulation: LH, 1059 mIU/ml; FSH, 3669 mIU/ml), and urinary steroid hormone profile analysis indicated grossly normal steroidogenic enzyme activities. The results suggest that SF-1 haploinsufficiency can selectively impair testicular development and permit the biosynthesis of AMH and testosterone in dysgenetic testes and the production of gonadotropins in pituitary gonadotropes.

	Introduction

Top Abstract Introduction Patient and Methods Results Discussion References

 
STEROIDOGENIC FACTOR-1 (SF-1), also known as adrenal 4-binding protein and formally designated as nuclear receptor subfamily 5 group A number 1 (NR5A1), is a monomeric orphan nuclear receptor that was initially identified as a key determinant of steroid hormone biosynthesis (1, 2). Subsequent studies have shown that Sf-1 regulates the transcription of a vast array of genes involved in adrenal and gonadal development, sex differentiation, steroidogenesis, and reproduction (1, 2, 3). Murine Sf-1 is expressed in the adrenals, gonads, pituitary gonadotropes, and ventromedial hypothalamic nucleus (VMH), and homozygous Sf-1 knockout mice show adrenal and gonadal agenesis, impaired function of pituitary gonadotropes, and abnormalities of VMH (1, 2, 3). They also show late-onset obesity when rescued by adrenal transplantation (4). In addition, heterozygous Sf-1 knockout mice exhibit a much milder phenotype (5).

To date, human SF-1 mutations have been reported in four patients. Achermann et al. (6, 7) identified a heterozygous G35E mutation and a homozygous R92Q mutation in two 46,XY patients with primary adrenal failure and gonadal dysgenesis, Biason-Lauder and Schoenle (8) found a heterozygous R255L mutation in a 46,XX patient with primary adrenal insufficiency and apparently normal ovarian development, and Correa et al. (9) detected a heterozygous 8-bp deletion mutation in a 46,XY patient with normal adrenal function and testicular regression syndrome. These findings suggest that SF-1 mutations and clinical features are variable among affected individuals.

However, SF-1 mutations identified in human patients are still limited in number, and additional studies are necessary to increase our knowledge about the molecular and clinical findings in human SF-1 mutations. Here, we report a novel SF-1 mutation in a patient identified by the mutation screening for 12 patients with 46,XY sex reversal without extragenital features.

	Patient and Methods

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Patient

This Japanese patient was born to nonconsanguineous parents after an uncomplicated term pregnancy. The parents and the two elder brothers were clinically normal. Although atypical genitalia were noticed at birth, the patient was reared as a female with no medical intervention. At 3 yr of age, she was seen at another hospital because of ambiguous genitalia. Genitoplasty was recommended at that time, but the parents refused a surgical intervention. Subsequently, the patient and her parents did not seek a medical examination until adulthood. Her pubertal development was complicated by poor breast development, lack of menarche, and advanced virilization, such as voice breakage and hirsutism. Apparently, she never had adrenal crisis even at the time of infections. She disliked wearing clothes for girls and enjoyed riding a motorcycle.

At 27 yr of age, she came to Asoka Hospital because of primary amenorrhea. She exhibited a eunuchoid habitus with a height of 174 cm (+0.6 SD for a male), a weight of 82 kg (+2.1 SD for a male), and a body mass index of 27. Breast development was at Tanner stage 2, and pubic hair development at Tanner stage 4. External genitalia were associated with clitoromegaly (2 cm long), but there was no labial fusion and the vaginal and the urethral orifices were separated (Fig. 1A). Small testis-like masses were palpable in the bilateral inguinal regions. She had no evidence of skin hyperpigmentation. Psychosexual development was assessed to be nonconforming by psychological studies. She identified herself as neither male nor female and had no sex partner. Pelvic magnetic resonance imaging delineated small testis-like structures in the inguinal regions and blind-ending vagina (6 cm deep) with no uterus. Her karyotype was 46,XY in all 50 lymphocytes examined. Serum sodium was 140 mEq/liter, serum potassium was 4.1 mEq/liter, serum chloride was 104 mEq/liter, and plasma glucose was 100 mg/dl (5.6 mmol/liter). Endocrine studies showed normal adrenal function and primary hypogonadism, and urinary steroid hormone profile analysis by a gas liquid chromatograph mass spectrometry (10) indicated grossly normal steroidogenic enzyme activities (Table 1). Genitoplasty was refused, but gonadectomy was carried out because of a risk for gonadal malignancy. Macroscopic examination revealed severely hypoplastic testes (right, 3 ml; left, 2 ml) accompanied by vasa deferentia and epididymides. Microscopic examination indicated dysgenetic testes consisting of severely hyalinized seminiferous tubules containing a few of Sertoli cells and loose interstitium containing a few of Leydig cells (Fig. 1B). Vasa deferentia and epididymides showed normal histological findings. Thereafter, she was placed on hormone replacement therapy, but compliance was poor because of reluctance to have breast development.

View larger version (60K): [in this window] [in a new window]   FIG. 1. Genital features of this patient. A, External genitalia. B, Testis histology.

This study was approved by the institutional review board committees at Keio University School of Medicine and National Center for Child Health and Development. After obtaining informed consent, leukocyte genomic DNA of this patient was amplified by PCR for all seven exons and their flanking introns of SF-1 (the primer sequences are available on request). Subsequently, the PCR products were subjected to direct sequencing from both directions on a CEQ 8000 Autosequencer (Beckman Coulter, Fullerton, CA). To confirm a heterozygous mutation, the corresponding PCR products were subcloned with a TOPO TA Cloning Kit (Invitrogen Life Technologies, Inc., Carlsbad, CA), and normal and mutant alleles were sequenced separately. The G146A polymorphism, which is known to decrease transactivation activity by approximately 20% (14), was also examined by direct sequencing. Furthermore, direct sequencing was also performed for SRY (15), LHX9 (16), and DMRT1 (17) in the screening of proven and candidate genes for XY gonadal dysgenesis without extragenital features. The parents refused molecular analysis, and DNA samples of 100 normal individuals were used with permission.

Western blot analysis

Western blot analysis was performed for protein extract of 293 human embryonic kidney (293 HEK) cells transiently transfected with an empty expression vector pCMX-PL2 (empty), an expression vector containing a mutant SF-1 cDNA (MT), and an expression vector containing a wild-type SF-1 cDNA (WT). The MT expression vector was created by site-directed mutagenesis using the WT expression vector, and the transfection was performed with a Gene Pulser II electroporation instrument (Bio-Rad Laboratories, Hercules, CA). The primary antibodies for SF-1 protein raised in a rabbit (18) were used at a 1:20,000 dilution and were detected by the secondary antibodies labeled with alkaline phosphatase (Promega Corp., Madison, WI).

Transcription analysis

Transcription activity was examined with Dual Luciferase Reporter Assay System (Promega Corp.). A luciferase reporter construct containing the SF-1 binding site 2 in the human CYP11A promoter (–110 to +49) (19) was created using pGL3 basic vector. The 293 HEK cells were transfected by electroporation with 1) the pCMX-PL2 empty expression vector and the reporter (empty reporter), 2) the WT expression vector and the reporter (WT-reporter), 3) the MT expression vector and the reporter (MT-reporter), 4) the WT plus MT (1:1) expression vectors and the reporter [WT:MT (1:1)-reporter], and 5) the WT plus MT (1:5) expression vectors and the reporter [WT:MT (1:5)-reporter] together with the pRL-cytomegalovirus vector used as an internal control for the transfection. Luciferase assays were performed 48 h later. The assays were repeated five times. The results are expressed as the mean ± SD, and statistical significance was determined by t test.

	Results

Top Abstract Introduction Patient and Methods Results Discussion References

 
Mutational analysis

The patient had a heterozygous single base pair deletion at exon 2 (18delC) that is predicted to cause a frameshift at the sixth codon for the aspartic acid and resultant termination at the 74th codon (D6fsX74; Fig. 2A). This mutation was absent in the 100 control subjects. The G146A polymorphism was present in a heterozygous condition, and it was uncertain whether the normal allele was accompanied by a glycine or an alanine residue as the 146th amino acid. No mutation was identified for SRY, LHX9, and DMRT1, nor was a polymorphism leading to amino acid substitution identified.

View larger version (36K): [in this window] [in a new window]   FIG. 2. Mutational analysis of SF-1 and functional study of the mutant SF-1. A, Mutational analysis. A single base pair deletion mutation of SF-1 has been indicated by the direct sequencing and confirmed by the sequencing of subcloned normal and mutant alleles. Because this mutation (18delC) is predicted to cause frameshift at the sixth codon for the aspartic acid and resultant termination at the 74th codon (D6fsX74), it should have lost all of the functional domains of the SF-1 protein. DBD, DNA-binding domain; LBD, ligand-binding domain. B, Western blot analysis. The arrow indicates the band for the normal SF-1 protein. Although several bands are detected for the MT, they are also identified for the empty and WT, and no band specific to MT is seen. MWM, Molecular weight marker. C, Transcription analysis. The upper chart shows a luciferase reporter construct containing the SF-1-binding site 2 in the human CYP11A promoter (–110 to +49). The lower chart indicates the normalized luciferase activity. The MT SF-1 has no transcription activity and exerts no dominant negative effect on the WT SF-1.

The SF-1 protein was detected for WT and undetected for empty and MT (Fig. 2B). Although several bands were delineated for MT, they were also identified for empty and WT, and no band specific to MT was identified.

Transcription analysis

The normalized luciferase activity was 0.30 ± 0.03 for empty reporter, 1.00 ± 0.19 for WT-reporter, 0.34 ± 0.08 for MT-reporter, 0.97 ± 0.31 for WT:MT (1:1)-reporter, and 1.05 ± 0.16 for WT:MT (1:5)-reporter (Fig. 2C). The activity was comparable between empty reporter and MT-reporter and between WT-reporter, WT:MT (1:1)-reporter, and WT:MT (1:5)-reporter and was significantly lower in MT-reporter than in WT-reporter, WT:MT (1:1)-reporter, and WT:MT (1:5)-reporter.

	Discussion

Top Abstract Introduction Patient and Methods Results Discussion References

 
A novel heterozygous SF-1 mutation, 18delC for D6fsX74, was identified in a 46,XY sex-reversed patient with dysgenetic testes. In this regard, it has been reported that when a mutation results in a premature truncation at a position very close to the natural translation start site, a partially functional protein deleted only for a small N-terminal fragment could be produced using an alternative translation initiation site (20). However, Western blot analysis indicated no evidence for the presence of such an amino-truncated SF-1 protein despite the18delC mutation being very close to the natural translation start codon. Furthermore, transcription analysis using the human CYP11A promoter indicated that the mutation was transcriptionally inactive and had no dominant negative effect, although it remains possible that the mutation has differential effects on different promoters (21). Thus, although there is a bias that mutation analysis was performed for 46,XY sex-reversed patients without extragenital features, the results indicate that SF-1 haploinsufficiency can cause testicular dysgenesis and a resultant XY sex reversal-only phenotype.

This patient had male-type genital duct development together with somewhat masculinized external genitalia. This implies that the dysgenetic testes were capable of producing a sufficient amount of anti-Mullerian hormone (AMH) for Mullerian regression and testosterone (T) for Wolffian development, although they were incapable of producing a sufficient amount of T for complete masculinization of external genitalia (22). Such T production would also be compatible with the psychosexual disturbance of this patient (22). Thus, although the biosynthesis of AMH and T is regulated by SF-1 (1, 2, 3), SF-1 haploinsufficiency in this patient, although it impaired gonadal development, is considered to have permitted the biosynthesis of a certain amount of AMH and T in the dysgenetic testes. In support of this, endocrine studies suggest that steroidogenic enzyme activities were grossly normal in this patient.

In contrast to testicular dysgenesis, adrenal function was well preserved in this patient. This is notable, because SF-1 is known to play a critical role in adrenal and gonadal development and steroidogenesis (1, 2, 3). One possibility for this discrepancy would be that the patient had a specific genetic background susceptible to the development of testicular dysgenesis. For example, the presence of a heterozygous recessive mutation and/or a hypofunctional polymorphism of a gene involved in testis development could raise the predisposition to testicular dysgenesis, although no sequence variation was detected in SRY, LHX9, and DMRT1. Another possibility would be that the patient had a particular genetic background resistant to the development of adrenal dysfunction. In addition, an environmental factor(s) such as focal circulation may have differed between the adrenals and gonads of this patient. In any case, the results imply that haploinsufficiency of a human developmental gene can be associated with a wide range of phenotypic variability among target organs as well as among affected individuals (23).

Furthermore, two findings are also noteworthy in this patient. First, she had obvious hypergonadotropinism. This suggests that gonadotropin production is fairly preserved in SF-1 haploinsufficiency, although gonadotropin production is regulated by SF-1 (1, 2, 3). Consistent with this, homozygous Sf-1 knockout mice can respond to GnRH stimulation (24). Second, she also had mild obesity. Although this may be related to sex steroid deficiency (25), the phenotype is reminiscent of late-onset obesity in homozygous Sf-1 knockout mice rescued by adrenal transplantation (4). Because such mice have a markedly altered structure of VMH that plays an important role in the regulation of appetite and body weight (26), impaired VMH function may be responsible for the mild obesity.

To date, human SF-1 mutations have been identified in five patients, including the present case (Table 2). Several points are noteworthy for the mutations. First, cases 1 and 3–5 have heterozygous mutations, whereas case 2 has a homozygous mutation. In this regard, functional studies have indicated that the mutation of case 3 has a dominant negative effect; the mutations of cases 1, 4, and 5 are virtually amorphic; and the mutation of case 2 is hypomorphic. This implies that the gene dosage and the residual SF-1 function play critical roles in the development of clinical features. Consistent with this, the heterozygous familial members of case 2 have no abnormal findings. Second, the mutations are different from each other. This suggests the absence of a mutation hot spot and the lack of a founder effect in SF-1 mutations that usually affect gonadal development. Third, cases 1, 4, and 5 with SF-1 haploinsufficiency have definite clinical features, whereas mice heterozygous for a null mutation have a much milder phenotype (5). This may imply that humans are more sensitive than mice to the SF-1 dosage effect, although there may be an ascertainment bias that only individuals with significant phenotype have been examined in the human.

In summary, we identified a novel SF-1 mutation in a 46,XY sex-reversed patient with testicular dysgenesis. The results, in conjunction with the previous data, imply that the human SF-1 mutations are variable, and that clinical features may primarily be ascribed to developmental defects of the target organs.

	Acknowledgments

 
We thank Dr. Toshihiko Yanase for providing us with the human SF-1 c-DNA, Ms. Keiko Homma for the urine steroid hormone profile analysis, and Dr. Michiyo Okada, Ms. Izumi Kobayashi, and Ms. Fumiko Kato for their technical assistance.

	Footnotes

 
This work was supported by a grant for Child Health and Development from the Ministry of Health, Labor, and Welfare (14C-1), a grant from the Mother and Child Health Foundation (15-2 and -9), Pfizer Fund for Growth and Development Research, and a Grant-in-Aid for Scientific Research on Priority Areas (16086215).

Abbreviations: AMH, Anti-Mullerian hormone; MT, mutant; SF-1, steroidogenic factor-1; T, testosterone; VMH, ventromedial hypothalamic nucleus; WT, wild type.

Received May 17, 2004.

Accepted September 9, 2004.

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