DAX1 and X-linked adrenal hypoplasia congenita: clinical and molecular analysis in five patients

in European Journal of Endocrinology
(Correspondence should be addressed to G Mantovani; Email: giovanna.mantovani@unimi.it)

Objective: Mutations in the gene coding for the orphan nuclear receptor DAX1 cause X-linked adrenal hypoplasia congenita (AHC). Affected boys usually present with primary adrenal failure in early infancy or childhood. Impaired sexual development due to hypogonadotropic hypogonadism becomes manifest at the time of puberty. Moreover, evidence from Dax1 knockout mice and a limited number of patients with AHC, suggests that mutations in DAX1 may directly cause abnormalities in spermatogenesis. The aim of this study was to characterize clinically and genetically five patients with AHC.

Design: DNA sequencing analysis, endocrine testing, testicular ultrasound and semen analysis with 1-year follow-up after gonadotropin treatment.

Methods: We report on five men with classic AHC manifestations. Genomic DNA was extracted from patients’ peripheral blood leukocytes and the coding region, splice sites, and promoter (−240 bp) region of DAX1 were directly sequenced.

Results: Three known and two novel mutations were detected in the DAX1 coding sequence in these patients. Semen analysis was performed in four of the five patients and showed azoospermia. Twelvemonth treatment with gonadotropins did not restore fertility in these patients. All patients showed a normal testicular Doppler ultrasound, in contrast with that observed in Dax1-deficient mice, which display abnormalities in the rete testis.

Conclusions: These cases further expand the number of DAX1 mutations reported in the literature, as well as our clinical knowledge of this rare disease.

Abstract

Objective: Mutations in the gene coding for the orphan nuclear receptor DAX1 cause X-linked adrenal hypoplasia congenita (AHC). Affected boys usually present with primary adrenal failure in early infancy or childhood. Impaired sexual development due to hypogonadotropic hypogonadism becomes manifest at the time of puberty. Moreover, evidence from Dax1 knockout mice and a limited number of patients with AHC, suggests that mutations in DAX1 may directly cause abnormalities in spermatogenesis. The aim of this study was to characterize clinically and genetically five patients with AHC.

Design: DNA sequencing analysis, endocrine testing, testicular ultrasound and semen analysis with 1-year follow-up after gonadotropin treatment.

Methods: We report on five men with classic AHC manifestations. Genomic DNA was extracted from patients’ peripheral blood leukocytes and the coding region, splice sites, and promoter (−240 bp) region of DAX1 were directly sequenced.

Results: Three known and two novel mutations were detected in the DAX1 coding sequence in these patients. Semen analysis was performed in four of the five patients and showed azoospermia. Twelvemonth treatment with gonadotropins did not restore fertility in these patients. All patients showed a normal testicular Doppler ultrasound, in contrast with that observed in Dax1-deficient mice, which display abnormalities in the rete testis.

Conclusions: These cases further expand the number of DAX1 mutations reported in the literature, as well as our clinical knowledge of this rare disease.

Introduction

The orphan nuclear receptor DAX1 plays a crucial role in the development and function of the adrenal gland and the hypothalamic–pituitary–gonadal axis (14). Mutations in the gene encoding DAX1 (DAX1, OMIM: 300473) cause X-linked adrenal hypoplasia congenita (AHC, OMIM: 300200) (1, 2). AHC is an inherited disorder of adrenal gland development, characterized by lack of the permanent zones of the adrenal cortex. Boys with this condition usually present with severe primary adrenal failure in infancy or childhood. Hypogonadotropic hypogonadism (HH) becomes apparent at puberty and infertility results from gonadotropin deficiency in combination with a primary defect in spermatogenesis (5, 6). Over 80 different mutations in DAX1 have been described, most of which are nonsense or frameshift mutations causing premature truncation of the protein (79).

During the last years, other variant phenotypes including an adult-onset form of AHC (1012), isolated HH in a female homozygous for a DAX1 mutation and extreme pubertal delay in heterozygous female carriers have been described (6, 13). Moreover, evidence from both Dax1 knockout mice (14) and a limited number of patients with AHC (6, 1012), suggests that mutations in DAX1 may directly cause abnormalities in spermatogenesis. In particular, either Sertoli cell (15) or Leydig cell (16) ‘rescue’ of Dax1 expression showed that these rescued animals have restored fertility, although abnormalities in testicular architecture persist. The way in which DAX1 affects fertility seems to be, at least in part, mediated by blockage of the rete testis, with subsequent dilatation of the proximal efferent ductules (17). Dilatation or ectasia of the rete testis, that is the anastomosing spaces where the tubuli recti enter the mediastinum testis, is a rare and benign condition that may be visualized on scrotal sonography. Interestingly, among all patients described to date in the literature, only one has been reported to show abnormalities of the rete testis, and in particular ectasia of the rete testis at testicular ultrasound (12), although most of these patients are not usually investigated for such an alteration.

Here, we report clinical and molecular analysis of five young males with classic AHC manifestations and HH due to DAX1 mutations, two of which have not previously been reported in the literature. This study further expands the present knowledge about the disease and reports two novel alterations in this gene.

Materials and methods

DNA sequencing and mutational analysis

After obtaining written consent, genomic DNA was extracted from peripheral blood leukocytes using standard procedures. Both exons of DAX1 (GenBank accession no. NM_000475) were amplified by PCR using specific oligonucleotide primer pairs and conditions described previously (11, 12). Direct sequencing of PCR products was performed using a Taq big dye terminator sequencing kit and an ABI310 automated sequencer (PE Applied Biosystems, Foster City, CA, USA).

Informed consent was obtained in all cases, after project approval by the local Ethics Committee.

Testicular ultrasound

Ultrasound of the scrotum has been reported to be highly sensitive in the detection of rete testis blockage (18) and it consisted of imaging the testes, epididymides, paratesticular structures and spermatic cords in a systematic fashion. The examination was performed with the patient supine and the scrotum elevated by a sheet wrapped around the patient’s pelvis. A 7 to 15 MHz. transducer was used. Transverse and longitudinal images were obtained, and color and spectral Doppler ultrasound was performed.

Results

Patients

The five patients presented either at neonatal age (patient 2) or childhood (patients 1, 3, 4 and 5) with a history of fatigue, nausea, dehydration and weight loss. Patient 4 has been extensively described in a previous report (19). Clinical laboratory investigations revealed hypocortisolemia, hypoaldosteronism and elevated adrenocorticotropin (ACTH) in all boys, consistent with primary adrenal failure. All patients later presented with delayed puberty, with low testosterone levels in the presence of low/normal follicle-stimulating hormone and luteinizing hormone (LH) levels, and both were unresponsive to gonadotropin releasing hormone (GnRH) stimulation test. All of them, with the exception of patient 2 who is still growing, reached a normal final height, consistent with their target height (Table 1). Androstenedione, progesterone and 17-hydroxyprogesterone were below the normal range. An abdominal computed tomography scan revealed small adrenal glands. Anti-adrenocortical antibodies were negative, and very-long-chain fatty acids were normal, thus excluding autoimmune Addison’s disease and adrenoleukodystropy respectively. Moreover, all patients underwent a testicular Doppler ultrasound. The typical appearance of the rete testis is an echogenic structure communicating from the mediastinum testis to the epididymal head. The rete is usually located at the posterolateral aspect of the testis. Occasionally, the rete may be anechoic with numerous tiny round or tubular structures, indicating tubular ectasia of the rete testis. Ultrasound of the five patients included in the study did not detect any abnormality of the rete testis.

Treatment with cortisone acetate and/or hydrocortisone and testosterone was started in all patients. Semen analysis was performed in four patients (1, 3, 4 and 5) and showed azoospermia. In these four patients, testosterone replacement was withdrawn and treatment with exogenous gonadotropins was started and maintained for at least one year (human chorionic gonadotropin 2000 IU and urofollitropin 75 IU, three times weekly). In all patients, this treatment failed to improve the sperm count and restore fertility. Consequently, intramuscular testosterone enanthate (250 mg every 4 weeks) replacement was restored. Of note, while 1-year treatment induced normalization of testosterone levels in patient 4, patients 1, 3 and 5 did not respond either in terms of hormonal testing, or in terms of testicular volume.

No patient had a family history of affected males. Clinical and endocrine details are given in Table 1.

Mutational analysis

Direct DNA sequencing analysis of DAX1 in patients 1, 2 and 4 revealed three frameshift alterations, of which two are deletions, the first novel to the literature, and one an insertion (1011delC, codon 337; 543delA, codon 181; 259insAGCG, codon 86) (19, 20). All lead to premature stop codons at positions 371 (1011delC) and 263 (543delA and 259insAGCG), thus resulting in non-functional truncated proteins. Patient 3 revealed a missense mutation in the C-terminal region of DAX1 (K382N), which has already been reported and shown to result in a protein devoid of repressor activity (21). In patient 5, we detected a C-terminal missense mutation (W291S), novel to the literature. Nevertheless, this codon, which is highly conserved among other related orphan nuclear receptor superfamily members, has already been demonstrated to be subject to substitution (W291C), resulting in a non-functional protein (21). A schematic representation of the human DAX1 gene is shown in Fig. 1.

Four of the five mothers of the affected boys were screened and shown to be heterozygous for the same mutations. At the time of the screening, patient 3’s mother had already died. No other family members were available for the study.

Discussion

The association of mutations in the orphan nuclear receptor DAX1 with X-linked AHC and hypogonadotropic hypogonadism (HH) is well established. Affected boys often present with salt-wasting primary adrenal insufficiency in early infancy (5, 22, 23). Children who do not present symptoms early in life may undergo a period of relatively good health and tend to present with more insidious signs and symptoms of the disease throughout childhood or, rarely, in adulthood. At puberty, boys also display delayed sexual development due to a combined hypothalamic and pituitary form of HH (5). The patients described here all presented with the classical, early-onset clinical and endocrine features (Table 1).

Direct DNA sequencing analysis revealed two novel and three known mutations in DAX1 (two deletions, one insertion and two missense mutations in the C-terminus) (1921). Most mutations of DAX1 are nonsense or frameshift mutations that cause premature truncation of the protein, and it has been demonstrated that deletion of as few as the last nine amino acids of DAX1, which constitute the putative activation function-2 domain, is associated with severe clinical phenotype (24). Therefore, the two deletions and the insertion described here are predicted to result in non-functional truncated proteins. On the other hand, the K382N missense mutation has already been reported and results in a protein devoid of repressor activity (21). In patient 5, we detected a missense mutation (W291S) novel to the literature. Nevertheless, this codon, which is highly conserved among other related orphan nuclear receptor superfamily members, has already been demonstrated to be subject to substitution (W291C), resulting in a non-functional protein (21). Our report of these two missense mutations further strengthens the hypothesis of a potential clustering of DAX1 missense mutants in the putative ligand binding domain.

Evidence from overexpression of DAX1/Dax1 in humans (25) and mice (26) has shown that this nuclear receptor plays a key dosage-sensitive role in gonadal development. Furthermore, targeted deletion of Dax1 in the mouse causes impaired spermatogenesis and infertility (14). Dax1 knockout mice have quite marked abnormalities of testicular structure, with dilated seminiferous tubules, blockage of the rete testis and of proximal/middle efferent tubules due to aberrantly located Sertoli cells, and ectopic and hyper-plastic Leydig cells (17). Both Sertoli and Leydig cell ‘rescue’ of Dax1 expression have been performed by crossing Dax1 knockout mice with transgenic lines expressing Dax1 from an anti-Müllerian hormone and an LH receptor promoter respectively (15, 16). These rescued animals have restored fertility, but the abnormalities in testicular architecture persist.

Limited data are available about the role of DAX1 in human fertility. Azoospermia has been reported in several patients with classic X-linked AHC, and attempts to induce fertility using gonadotropins have been unsuccessful to date in a limited number of patients (6, 1012, 27). Given the Dax1 knockout mice phenotype, it could be expected that blockage of the rete testis should be a hallmark in AHC patients. Interestingly, of all patients described to date in the literature, only one has been reported to show blockage of the rete testis at testicular ultrasound (12), although most of them were not evaluated for such an alteration. Our report of a normal testicular Doppler ultrasound in all five patients described does not seem to support this hypothesis. On the contrary, the lack of effect on spermatogenesis of one-year treatment with gonadotropins in four of our patients provides further evidence that DAX1 directly affects spermatogenesis in man and that these patients are relatively resistant to gonadotropin treatment. The observed increase in circulating testosterone values during treatment indicates that Leydig cell function can be, at least partially, rescued in some of these patients, suggesting that Leydig cell defects are mainly dependent on gonadotropin deficiency, at least in humans. Therefore, gonadotropin treatment may be able to rescue, partially, the Leydig cell function but not the exocrine function.

The lack of blockage of the rete testis in our DAX1-deficient men seems to indicate that human spermatogenesis also does not depend on factors connected with structural disorganization of the gonads. A testicular biopsy could provide additional information to reveal the mechanism underlying spermatogenic failure in these patients. To date, the only data on testicular histology in DAX1-deficient men have been reported by Brown and colleagues (27) who described normal testicular architecture in an infant who died of AHC. Accordingly, the ‘rescue’ experiments in DAX1 knockout mice seem to exclude the possibility that abnormalities of the testicular structure are mainly responsible for their infertility. Unfortunately, this hypothesis could not be confirmed by our study since none of our patients underwent a testicular biopsy, as there was no existing clinical and ethically correct indication for this invasive procedure. A testicular specimen could be obtained perhaps in the future if the patients opt for intracytoplasmic sperm injection, but, at the moment, none of the patients included in this study is seeking paternity.

This report further expands the number of DAX1 mutations reported in the literature, and adds to our clinical knowledge of this rare disease. Further studies will seek to clarify the real impact of DAX1 mutations on human spermatogenesis, in order to achieve the appropriate management of fertility in these patients.

Acknowledgements

This work was supported by a research grant from the Italian Ministry of Instruction, University and Research (MIUR) (grant 2002068221-001 to L P) and Research Funds of the Ospedale Maggiore IRCCS and Istituto Auxologico Italiano IRCCS, Milan.

Table 1

Clinical, biochemical and molecular data of AHC patients included in the study. The endocrine data refer to the first evaluation in an adult endocrine unit, after replacement therapies were withdrawn.

Treatment with Gn
Patient no.Age at diagnosis (years)Present age (years)Height/target (cm)Cortisol (nmol/l) (nv: 140–700)ACTH (ng/l) (nv: 10–65)Testosterone (nmol/l) (nv: 13–42)Testes vol. (ml)Blockage of the rete testisSperm countSperm count↑ TestosteroneDAX1Mutation
nv, normal values; NP, not performed; Gn, gonadotropins.
*Patient #2 is still growing. **These patients were treated both with gonadotropins and, subsequently, with GnRH.
11319176/1764919003.12NoAzoospermiaNo responseNo response1011delC
2<0.118167*/174<1010633.06NoNPNPNP543delA
3134174/177<107900.73NoAzoospermiaNo response**No response**K382N
4339178/175<1024 9800.63NoAzoospermiaNo responseResponse259insAGCG
5539178/176<109700.75NoAzoospermiaNo response**No response**W291S
Figure 1

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Figure 1

Schematic representation of the human DAX1 gene. The amino-terminal repeat motif is shown. The positions of the 5 mutations described in this report are also shown. LBD, ligand binding domain; DBD, DNA binding domain.

Citation: European Journal of Endocrinology eur j endocrinol 154, 5; 10.1530/eje.1.02132

References

  • 1

    ZanariaE Muscatelli F Bardoni B Strom TM Guioli S Guo W Lalli E Moser C Walker AP & McCabe ER. An unusual member of the nuclear hormone receptor superfamily responsible for X-linked adrenal hypoplasia congenita. Nature1994372635–641.

  • 2

    MuscatelliF Strom TM Walker AP Zanaria E Recan D Meindl A Bardoni B Guioli S Zehetner G & Rabl W. Mutations in the DAX-1 gene give rise to both X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism. Nature1994372672–676.

  • 3

    GuoW Burris TP & McCabe ER. Expression of DAX-1 the gene responsible for X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism in the hypothalamic–pituitary–adrenal/gonadal axis. Biochemistry and Molecular Medicine1995568–13.

  • 4

    SwainA Zanaria E Hacker A Lovell-Badge R & Camerino G. Mouse Dax1 expression is consistent with a role in sex determination as well as in adrenal and hypothalamus function. Nature Genetics199612404–409.

  • 5

    HabibyRL Boepple P Nachtigall L Sluss PM Crowley WF Jr & Jameson JL. Adrenal hypoplasia congenita with hypogonadotropic hypogonadism: evidence that DAX-1 mutations lead to combined hypothalamic and pituitary defects in gonadotropin production. Journal of Clinical Investigations1996981055–1062.

  • 6

    SeminaraSB Achermann JC Genel M Jameson JL & Crowley WF Jr. X-linked adrenal hypoplasia congenita: a mutation in DAX1 expands the phenotypic spectrum in males and females. Journal of Clinical Endocrinology and Metabolism1999844501–4509.

  • 7

    PhelanJK & McCabe ER. Mutations in NR0B1 (DAX1) and NR5A1 (SF1) responsible for adrenal hypoplasia congenita. Human Mutation200118472–487.

  • 8

    KroneN Riepe FG Dorr HG Morlot M Rudorff KH Drop SL Weigel J Pura M Kreze A Boronat M de Luca F Tiulpakov A Partsch CJ Peter M & Sippell WG. Thirteen novel mutations in the NR0B1 (DAX1) gene as cause of adrenal hypoplasia congenita. Human Mutation200525502–503.

  • 9

    BalsamoA Antelli A Baldazzi L Baronio F Lazareva D Cassio A & Cicognani A. A new DAX1 gene mutation associated with congenital adrenal hypoplasia and hypogonadotropic hypogonadism. American Journal of Medical Genetics2005135292–296.

  • 10

    TabarinA Achermann JC Recan D Bex V Bertagna X Christin-Maitre S Ito M Jameson JL & Bouchard P. A novel mutation in DAX1 causes delayed-onset adrenal insufficiency and incomplete hypogonadotropic hypogonadism. Journal of Clinical Investigation2000105321–328.

  • 11

    MantovaniG Ozisik G Achermann JC Romoli R Borretta G Persani L Spada A Jameson JL & Beck-Peccoz P. Hypogonadotropic hypogonadism as a presenting feature of late-onset X-linked adrenal hypoplasia congenita. Journal of Clinical Endocrinology and Metabolism20028744–48.

  • 12

    OzisikG Mantovani G Achermann JC Persani L Spada A Weiss J Beck-Peccoz P & Jameson JL. An alternate translation initiation site circumvents an amino terminal DAX1 nonsense mutation leading to a mild form of X-linked adrenal hypoplasia congenita. Journal of Clinical Endocrinology and Metabolism200388417–423.

  • 13

    MerkeDP Tajima T Baron J & Cutler GB Jr. Hypogonadotropic hypogonadism in a female caused by an X-linked recessive mutation in the DAX1 gene. New England Journal of Medicine19993401248–1252.

  • 14

    YuRN Ito M Saunders TL Camper SA & Jameson JL. Role of Ahch in gonadal development and gametogenesis. Nature Genetics199820353–357.

  • 15

    JeffsB Ito M Yu RN Martinson FA Wang ZJ Doglio LT & Jameson JL. Sertoli cell-specific rescue of fertility but not testicular pathology in Dax1 (Ahch)-deficient male mice. Endocrinology20011422481–2488.

  • 16

    MeeksJJ Russell TA Jeffs B Huhtaniemi I Weiss J & Jameson JL. Leydig cell-specific expression of DAX1 improves fertility of the Dax1-deficient mouse. Biology of Reproduction200369154–160.

  • 17

    JeffsB Meeks JJ Ito M Martinson FA Matzuk M Jameson JL & Russell LD. Blockage of the rete testis and efferent ductules by ectopic Sertoli and Leydig cells causes infertility in Dax1-deficient male mice. Endocrinology20011424486–4495.

  • 18

    BurrusJK Lockhart ME Kenney PJ & Kolettis PN. Cystic ectasia of the rete testis: clinical and radiographic features. Journal of Urology20021681436–1438.

  • 19

    De MenisE Roncaroli F Calvari V Chiarini V Pauletto P Camerino G & Cremonini N. Corticotroph adenoma of the pituitary in a patient with X-linked adrenal hypoplasia congenita due to a novel mutation of DAX-1 gene. European Journal of Endocrinology2005153211–215.

  • 20

    ZhangYH Guo W Wagner RL Huang BL McCabe L Vilain E Burris TP Anyane-Yeboa K Burghes AH Chitayat D Chudley AE Genel M Gertner JM Klingensmith GJ Levine SN Nakamoto J New MI Pagon RA Pappas JG Quigley CA Rosenthal IM Baxter JD Fletterick RJ & McCabe ER. DAX1 mutations map to putative structural domains in a deduced three-dimensional model. American Journal of Human Genetics199862855–864.

  • 21

    NakaeJ Abe S Tajima T Shinohara N Murashita M Igarashi Y Kusuda S Suzuki J & Fujieda K. Three novel mutations and a de novo deletion mutation of the DAX-1 gene in patients with X-linked adrenal hypoplasia congenita. Journal of Clinical Endocrinology and Metabolism199723835–3841.

  • 22

    PeterM Viemann M Partsch CJ & Sippell WG. Congenital adrenal hypoplasia: clinical spectrum experience with hormonal diagnosis and report on new point mutations of the DAX-1 gene. Journal of Clinical Endocrinology and Metabolism1998832666–2674.

  • 23

    WiltshireE Couper J Rodda C Jameson JL & Achermann JC. Variable presentation of X-linked adrenal hypoplasia congenita. Journal of Pediatric Endocrinology and Metabolism2001141093–1096.

  • 24

    NakaeJ Tajima T Kusuda S Kohda N Okabe T Shinohara N Kato M Murashita M Mukai T Imanaka K & Fujieda K. Truncation at the C-terminus of the DAX-1 protein impairs its biological actions in patients with X-linked adrenal hypoplasia congenita. Journal of Clinical Endocrinology and Metabolism1996813680–3685.

  • 25

    BardoniB Zanaria E Guioli S Floridia G Worley KC Tonini G Ferrante E Chiumello G McCabe ER & Fraccaro M. A dosage sensitive locus at chromosome Xp21 is involved in male to female sex reversal. Nature Genetics19947497–501.

  • 26

    SwainA Narvaez V Burgoyne P Camerino G & Lovell-Badge R. Dax1 antagonizes Sry action in mammalian sex determination. Nature1998391761–767.

  • 27

    BrownP Scobie GA Townsend J Bayne RA Seckl JR Saunders PT & Anderson RA. Identification of a novel missense mutation that is as damaging to DAX-1 repressor function as a nonsense mutation. Journal of Clinical Endocrinology and Metabolism2003881341–1349.

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    Schematic representation of the human DAX1 gene. The amino-terminal repeat motif is shown. The positions of the 5 mutations described in this report are also shown. LBD, ligand binding domain; DBD, DNA binding domain.

References

1

ZanariaE Muscatelli F Bardoni B Strom TM Guioli S Guo W Lalli E Moser C Walker AP & McCabe ER. An unusual member of the nuclear hormone receptor superfamily responsible for X-linked adrenal hypoplasia congenita. Nature1994372635–641.

2

MuscatelliF Strom TM Walker AP Zanaria E Recan D Meindl A Bardoni B Guioli S Zehetner G & Rabl W. Mutations in the DAX-1 gene give rise to both X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism. Nature1994372672–676.

3

GuoW Burris TP & McCabe ER. Expression of DAX-1 the gene responsible for X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism in the hypothalamic–pituitary–adrenal/gonadal axis. Biochemistry and Molecular Medicine1995568–13.

4

SwainA Zanaria E Hacker A Lovell-Badge R & Camerino G. Mouse Dax1 expression is consistent with a role in sex determination as well as in adrenal and hypothalamus function. Nature Genetics199612404–409.

5

HabibyRL Boepple P Nachtigall L Sluss PM Crowley WF Jr & Jameson JL. Adrenal hypoplasia congenita with hypogonadotropic hypogonadism: evidence that DAX-1 mutations lead to combined hypothalamic and pituitary defects in gonadotropin production. Journal of Clinical Investigations1996981055–1062.

6

SeminaraSB Achermann JC Genel M Jameson JL & Crowley WF Jr. X-linked adrenal hypoplasia congenita: a mutation in DAX1 expands the phenotypic spectrum in males and females. Journal of Clinical Endocrinology and Metabolism1999844501–4509.

7

PhelanJK & McCabe ER. Mutations in NR0B1 (DAX1) and NR5A1 (SF1) responsible for adrenal hypoplasia congenita. Human Mutation200118472–487.

8

KroneN Riepe FG Dorr HG Morlot M Rudorff KH Drop SL Weigel J Pura M Kreze A Boronat M de Luca F Tiulpakov A Partsch CJ Peter M & Sippell WG. Thirteen novel mutations in the NR0B1 (DAX1) gene as cause of adrenal hypoplasia congenita. Human Mutation200525502–503.

9

BalsamoA Antelli A Baldazzi L Baronio F Lazareva D Cassio A & Cicognani A. A new DAX1 gene mutation associated with congenital adrenal hypoplasia and hypogonadotropic hypogonadism. American Journal of Medical Genetics2005135292–296.

10

TabarinA Achermann JC Recan D Bex V Bertagna X Christin-Maitre S Ito M Jameson JL & Bouchard P. A novel mutation in DAX1 causes delayed-onset adrenal insufficiency and incomplete hypogonadotropic hypogonadism. Journal of Clinical Investigation2000105321–328.

11

MantovaniG Ozisik G Achermann JC Romoli R Borretta G Persani L Spada A Jameson JL & Beck-Peccoz P. Hypogonadotropic hypogonadism as a presenting feature of late-onset X-linked adrenal hypoplasia congenita. Journal of Clinical Endocrinology and Metabolism20028744–48.

12

OzisikG Mantovani G Achermann JC Persani L Spada A Weiss J Beck-Peccoz P & Jameson JL. An alternate translation initiation site circumvents an amino terminal DAX1 nonsense mutation leading to a mild form of X-linked adrenal hypoplasia congenita. Journal of Clinical Endocrinology and Metabolism200388417–423.

13

MerkeDP Tajima T Baron J & Cutler GB Jr. Hypogonadotropic hypogonadism in a female caused by an X-linked recessive mutation in the DAX1 gene. New England Journal of Medicine19993401248–1252.

14

YuRN Ito M Saunders TL Camper SA & Jameson JL. Role of Ahch in gonadal development and gametogenesis. Nature Genetics199820353–357.

15

JeffsB Ito M Yu RN Martinson FA Wang ZJ Doglio LT & Jameson JL. Sertoli cell-specific rescue of fertility but not testicular pathology in Dax1 (Ahch)-deficient male mice. Endocrinology20011422481–2488.

16

MeeksJJ Russell TA Jeffs B Huhtaniemi I Weiss J & Jameson JL. Leydig cell-specific expression of DAX1 improves fertility of the Dax1-deficient mouse. Biology of Reproduction200369154–160.

17

JeffsB Meeks JJ Ito M Martinson FA Matzuk M Jameson JL & Russell LD. Blockage of the rete testis and efferent ductules by ectopic Sertoli and Leydig cells causes infertility in Dax1-deficient male mice. Endocrinology20011424486–4495.

18

BurrusJK Lockhart ME Kenney PJ & Kolettis PN. Cystic ectasia of the rete testis: clinical and radiographic features. Journal of Urology20021681436–1438.

19

De MenisE Roncaroli F Calvari V Chiarini V Pauletto P Camerino G & Cremonini N. Corticotroph adenoma of the pituitary in a patient with X-linked adrenal hypoplasia congenita due to a novel mutation of DAX-1 gene. European Journal of Endocrinology2005153211–215.

20

ZhangYH Guo W Wagner RL Huang BL McCabe L Vilain E Burris TP Anyane-Yeboa K Burghes AH Chitayat D Chudley AE Genel M Gertner JM Klingensmith GJ Levine SN Nakamoto J New MI Pagon RA Pappas JG Quigley CA Rosenthal IM Baxter JD Fletterick RJ & McCabe ER. DAX1 mutations map to putative structural domains in a deduced three-dimensional model. American Journal of Human Genetics199862855–864.

21

NakaeJ Abe S Tajima T Shinohara N Murashita M Igarashi Y Kusuda S Suzuki J & Fujieda K. Three novel mutations and a de novo deletion mutation of the DAX-1 gene in patients with X-linked adrenal hypoplasia congenita. Journal of Clinical Endocrinology and Metabolism199723835–3841.

22

PeterM Viemann M Partsch CJ & Sippell WG. Congenital adrenal hypoplasia: clinical spectrum experience with hormonal diagnosis and report on new point mutations of the DAX-1 gene. Journal of Clinical Endocrinology and Metabolism1998832666–2674.

23

WiltshireE Couper J Rodda C Jameson JL & Achermann JC. Variable presentation of X-linked adrenal hypoplasia congenita. Journal of Pediatric Endocrinology and Metabolism2001141093–1096.

24

NakaeJ Tajima T Kusuda S Kohda N Okabe T Shinohara N Kato M Murashita M Mukai T Imanaka K & Fujieda K. Truncation at the C-terminus of the DAX-1 protein impairs its biological actions in patients with X-linked adrenal hypoplasia congenita. Journal of Clinical Endocrinology and Metabolism1996813680–3685.

25

BardoniB Zanaria E Guioli S Floridia G Worley KC Tonini G Ferrante E Chiumello G McCabe ER & Fraccaro M. A dosage sensitive locus at chromosome Xp21 is involved in male to female sex reversal. Nature Genetics19947497–501.

26

SwainA Narvaez V Burgoyne P Camerino G & Lovell-Badge R. Dax1 antagonizes Sry action in mammalian sex determination. Nature1998391761–767.

27

BrownP Scobie GA Townsend J Bayne RA Seckl JR Saunders PT & Anderson RA. Identification of a novel missense mutation that is as damaging to DAX-1 repressor function as a nonsense mutation. Journal of Clinical Endocrinology and Metabolism2003881341–1349.

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