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Original Studies |
Division of Endocrinology, Metabolism, and Molecular Medicine (A.T.R., J.C.A., Ma.I., Mi.I., W.-X.G., R.L.H., J.L.J.), Northwestern University Medical School, Chicago, Illinois 60611; London Centre for Paediatric Endocrinology and Metabolism (J.C.A., P.C.H.), University College London, London, United Kingdom W1N 8AA; Department of Pediatrics (P.A.D.), University of Iowa College of Medicine, Iowa City, Iowa, 52242; and Department of Pediatrics (S.P.), University of Illinois College of Medicine, Chicago, Illinois 60612
Address all correspondence and requests for reprints to: J. Larry Jameson, M.D., Ph.D., Endocrinology, Metabolism, and Molecular Medicine, Northwestern University Medical School, 303 East Chicago Avenue, Tarry Building 15-709, Chicago, IL 60611. E-mail: ljameson{at}nwu.edu
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The genetic locus for X-linked AHC was mapped to Xp21 through studies of male patients with contiguous gene deletion syndromes (glycerol kinase deficiency, Duchenne muscular dystrophy, ornithine transcarbamylase deficiency, and mental retardation) (7, 8, 9). This region of the X chromosome is also the location of the dosage-sensitive sex reversal (DSS) locus important in sex determination (10, 11). In 1994, the human DAX-1 (DSS–AHC critical region on the X chromosome, gene 1) gene was cloned and mutations in DAX-1 were identified as causing both AHC and the associated hypogonadotropic hypogonadism (12, 13). This gene encodes a 470 amino acid protein, with approximately 50% homology between the carboxy-terminal region of DAX-1 and the ligand-binding domain (E domain) of the nuclear hormone receptor superfamily (12, 14, 15). DAX-1 is classified as an orphan nuclear receptor because no specific ligand has been identified to date (16). However, unlike other members of this family, DAX-1 lacks a typical zinc-finger DNA-binding domain. The unique amino-terminal portion of DAX-1 contains 31/2 repeats of a 65–67 amino acid motif (12) that may bind to hairpin loop structures in DNA (17).
DAX-1 plays a key role in the development of the adrenal gland and the hypothalamo-pituitary-gonadal axis. It is expressed in the developing urogenital ridge, ovary, testis, adrenal cortex, hypothalamus, and anterior pituitary gland (18, 19), and it colocalizes with another nuclear receptor protein, steroidogenic factor-1 (SF-1) (20). SF-1 regulates the expression of steroidogenic enzymes (21, 22, 23). Targeted disruption of the gene in mice leads to complete adrenal and gonadal agenesis, persistence of Müllerian structures in male mice (24), impaired expression of gonadotrope-specific markers in the anterior pituitary (25), and disruption of the hypothalamic ventromedial nucleus (26). Recently, in vitro studies showed that DAX-1 and SF-1 bind to one another through protein–protein interactions (27, 28, 29). DAX-1 has been shown to repress SF-1-mediated transactivation (27, 28, 29, 30). A repression domain has been localized to the carboxy-terminus of DAX-1 (17, 27), a region that is deleted in many patients with AHC. In this report, we describe the clinical features and genetic analyses in six racially and geographically diverse families with DAX-1 mutations who had early- and late-onset adrenal insufficiency. The functional effects of these mutations were examined using transient expression assays of SF-1-mediated transcription.
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Materials and Methods |
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After obtaining Institutional Review Board approval and informed consent from patients and family members, DNA was extracted from blood leukocytes. The 3 kb DAX-1 intron was amplified by PCR using a GeneAmp XL kit (Perkin Elmer, Foster City, CA) to allow the design of intronic oligonucleotide primers. Exons 1 and 2 of the DAX-1 gene were amplified from genomic DNA using the M13-tagged primers shown below (M13 sequence is not shown):
DAX 1.1 For: 5'-GCT CCC ACG CTG CTG TTC TTC-3'
DAX 1.1 Rev: 5'-CCG CCC ACC CGG AAG CCC CGC-3'
DAX 1.2 For: 5'-CGA AGG CGC CCG AGG CGA CGC-3'
DAX 1.2 Rev: 5'-GGA CGC CCA GCA GTT GCG CAC-3'
DAX 1.3 For: 5'-CGC TTC GTC AAG TAC TTG CCC-3'
DAX 1 Splice Rev: 5'-GTG TAG AGA GCC AAG TAC-3'
DAX 2 Splice For: 5'-TCC ACA CGT GTG CAT AGA AAC-3'
DAX 2 Splice Rev: 5'-TGT ACA GAG CTA TGC TAC CTG-3'
PCR was performed in a 100-µL reaction containing 100 ng genomic DNA, 50 pmol primers, 50 µM dNTPs, 1.1 mM MgCl2, and 5 U Taq polymerase (Promega, Madison, WI) in a buffer containing 10 mM Tris-HCl (pH 9.0), 50 mM KCl, 5% dimethylsulfoxide, and 0.1% Triton X-100. PCR conditions were 1 min predenaturation at 96 C, nine cycles of 1 min at 94 C, annealing for 1 min at 60 C, extension for 1 min at 72 C, 26 cycles of 1 min at 94 C, annealing (55–57.5 C) for 1 min, extension for 1 min at 72 C, and 15 min elongation at 72 C. Direct DNA sequencing was performed with Dye Primer Cycle Sequencing kits (Perkin Elmer) using an automated sequencer (Applied Biosystems Model 373A DNA Sequencer, Foster City, CA). For each exon, products from three different PCR reactions were sequenced in both directions. Sequences obtained from members of each kindred were compared with those from two unrelated normal control subjects. In potential heterozygotes, results of direct DNA sequencing were confirmed by subcloning purified PCR products into the pCR II vector (TA cloning kit, Invitrogen, San Diego, CA), and Taq cycle sequencing was performed on both strands as described above. At least eight subclones were sequenced.
Plasmid construction and transient expression assays
Eukaryotic expression vectors for the DAX-1 mutants were constructed from the pBKCMV (-lacZ promoter) human DAX-1 cDNA vector as described previously (27). The mutations were created by the overlapping PCR technique using primers containing the appropriate nucleotide substitutions. PCR-amplified mutant fragments were digested with restriction enzymes and inserted into the wild-type cDNA sequence. Construction of the expression vector for the GAL4-SF-1 fusion protein and the reporter construct UAS-TK109luc has been described (27).
Human choriocarcinoma JEG-3 cells (American Type Culture Collection HTB 36) were maintained in DMEM supplemented with 10% fetal bovine serum and 1% penicillin and streptomycin in a 5% CO2 atmosphere at 37 C. Cells were transfected with 500 ng UAS-TK109luc, 50 ng pSG424-GAL4 or GAL4-SF-1, and 20 ng pBKCMV expression vector (empty vector, DAX-1 wild type or DAX-1 mutant) using calcium phosphate precipitation as described previously (27). Each individual transfection reaction was performed in triplicate. Cell extracts were prepared 24 h after transfection, and luciferase assays were performed. The mean luciferase activity of each triplicate reaction was expressed as a percentage of GAL4-SF-1 to allow comparison of data from different experiments. The results represent the mean ± SEM from four different experiments, each consisting of triplicate transfections.
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Results |
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Individuals from six families with suspected X-linked AHC were
studied. The pedigrees of four families are shown in Fig. 1
. Clinical details of individual
presentations are summarized in Table 1,
and investigations of adrenal and gonadal function are shown in Tables 1 and 2, respectively.
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Half-brothers in kindred DK (III-1, III-3) were of American Caucasian origin and had a similar early clinical presentation. In patient DK:III-1, a diagnosis of 21-hydroxylase deficiency was made initially but was revised when he failed to enter puberty. His brother (DK:III-3) had normal electrolytes and cortisol at birth but developed hyperkalemia at 1 week of age.
Both BK brothers (IV-2, IV-3) presented in the first 2 weeks of life.
They were also from an American Caucasian family. BK:IV-2 presented in
a salt-losing crisis at 2 weeks of age but responded well to steroid
replacement. His younger brother (IV-3) had normal electrolytes and
cortisol (30 µg/dl) 24 h after birth but presented 2 weeks later
with meningitis, seizures, and a salt-losing crisis. Of note, an older
brother (IV-1) had died of congenital adrenal insufficiency and had
hypoplastic adrenal glands at autopsy. Two maternal uncles (III-3,
III-4) died in the first 2 days of life and had similar findings, and a
cousin of their mother (III-1) was diagnosed with Addison’s disease at
the age of 7 yr. BK:IV-2 failed to develop puberty. He showed little
response to GnRH stimulation and remains on testosterone replacement
(Table 2
). BK:IV-3 has severe learning difficulties after a head injury
in childhood, and no formal investigations have been performed; at 24
yr of age he remains prepubertal.
Kindred LS are of Mexican descent and were older at the time of diagnosis. The eldest son (IV-1) presented at the age of 2.5 yr with vomiting, dehydration, and shock, and a diagnosis of primary adrenal insufficiency was made. Cortisol was undetectable and ACTH was elevated. His maternal uncle (III-2) had been given a diagnosis of Addison’s disease when 2 yr old, and his great uncle (II-1) had died unexpectedly at 2 months of age from gastroenteritis. When his younger brother (IV-2) became hyperpigmented at 1 yr of age, the diagnosis of adrenal insufficiency was made, although he was otherwise asymptomatic at the time.
Patient LP was born in Scotland. He was diagnosed with craniosynostosis and developed cyanosis while under sedation for a cranial computed tomographic scan. He had repeated vomiting, cyanotic episodes, and epileptic seizures thereafter, but improved with glucocorticoid, mineralocorticoid, and salt replacement and underwent corrective surgery uneventfully.
SS, the eldest son in a family of Asian Indian descent, also had a
delayed presentation. He was diagnosed with adrenal insufficiency at
the age of 7 yr after a hypotensive episode and hyponatremia during an
acute asthma attack. Peak cortisol response to ACTH stimulation was 3.2
ng/dl, and he was started on glucocorticoid and mineralocorticoid
replacement. Although hyponatremia had been noted during an episode of
Escherichia coli septicemia at 6 days of age, he had been
well in early childhood but had developed progressive malaise before
presentation. He improved on treatment but grew poorly and was
reinvestigated at the age of 10 yr. Steroid replacement was temporarily
withdrawn, and primary adrenal insufficiency was confirmed (Table 1).
On steroid replacement, an unprimed insulin tolerance test produced a
suboptimal peak GH response of 5.1 mU/L (1 ng/ml = 2.6 mU/L)
(Hybritech Tandem-R, Liege, Belgium), and growth hormone treatment was
started. However, his failure to enter puberty led to the diagnosis of
X-linked AHC. He was shown to have a poor gonadotropin response to GnRH
and a moderate testosterone response to three doses of hCG (Table 2).
Virilization was induced with testosterone, and reevaluation at 18 yr
of age confirmed hypogonadotropic hypogonadism and revealed a
borderline GH response to stimulation (11.8 mU/L). At the age of 22 yr,
he reached a predicted height of 170.6 cm and remains on testosterone
replacement.
Mutational analyses
The DAX-1 gene was sequenced in each of the probands
and in available family members. The sequence findings are summarized
in Table 1. Nonsense mutations that introduce a stop codon were found
in three cases, and frameshift mutations were found in three cases.
These mutations, along with others reported in the literature, are
summarized in Fig. 2. The recommendations
of Antonarakis (31) were adopted to provide a consistent approach to
nucleotide numbering, because the designation of DAX-1
mutations differs in various original reports. In this system, the A of
the ATG translational initiation codon is designated as nucleotide
+1.
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TAG conversion at
nucleotide 512 resulted in a premature stop codon at codon 171 in place
of tryptophan. This mutation was not found in the patient’s mother or
brother, suggesting that she was not a carrier, and that it may have
arisen de novo in the affected patient. However, the
demonstration of gonadal mosaicism for this disease by Zhang et al.
(32) indicates that females who are shown not to be carriers for
DAX-1 mutations are potentially at risk of having affected
sons, and such families should be counseled appropriately. In the DK
kindred, a nonsense mutation was also found in codon 171. However, in
this case, the substitution was TGG TGA at
nucleotide 513. This eliminated an Xcm I site and allowed
the screening of additional family members by restriction enzyme
analysis. The proband’s mother (II-2), grandmother (I-1), and a
maternal aunt (II-1) were found to be carriers (Fig. 1).
In LP, a nucleotide transversion at position 1197 (C A) resulted in
a novel mutation, introducing a stop codon at amino acid 399 within the
putative ligand-binding domain of DAX-1. Other family members were not
available for screening.
RG had a novel deletion of thymidine at nucleotide 405, causing a
frameshift and premature stop codon at amino acid 263. His mother was
heterozygous for this mutation, and a maternal aunt, pregnant at the
time of the study, was also found to be a carrier of the mutation. His
father was hemizygous and his mother heterozygous for the T C
polymorphism at nucleotide 114.
In the BK kindred, a deletion of adenosine at nucleotide 501 resulted
in a frameshift and premature stop codon at amino acid 263. Affected
males (IV-2, IV-3) were hemizygous for this deletion, and carrier
females (II-1, III-5) were heterozygous. A cousin of their mother
(III-2), pregnant at the time of the study, was not a carrier of this
mutation. She gave birth to a healthy baby boy. Silent polymorphisms
were found in one brother (IV-3, G A at nucleotide 498) and in his
mother (III-5, T C at nucleotide 114).
In the LS kindred, all three affected males (III-2, IV-1, IV-2) were
hemizygous for a previously unreported deletion of cytosine at
nucleotide 702, causing a frameshift and premature stop codon, again at
amino acid 263. As predicted from X-linked inheritance, both the mother
and grandmother were heterozygous for this frameshift deletion, but it
was not found in the unaffected baby boy (IV-3). Two silent
polymorphisms were also detected in this kindred; a T C
transversion at nucleotide 114 was identified in all members, and III-1
and II-2 were homozygous for this polymorphism. A G A transversion
at nucleotide 498 was present in all members apart from the unaffected
baby. The mother and grandmother were heterozygous for this
polymorphism.
Function of DAX-1 mutations
DAX-1 has been shown to inhibit the transcription of reporter
genes that are driven by SF-1 (17, 27, 28, 29). Therefore, we tested
whether the mutations in these patients altered this property of DAX-1
(Fig. 3). The W171X (kindreds SS and DK),
Y399X (kindred LP), and 702delC (patient LS, truncation at codon 263)
mutations were inserted into a DAX-1 expression plasmid.
GAL4-SF-1-driven expression of the UAS-TKLuc reporter gene was used to
assay for SF-1-mediated transactivation. GAL4-SF-1 alone stimulated the
reporter gene 18-fold when compared with the GAL4 DNA-binding domain
construct. Coexpression of wild-type DAX-1 greatly repressed SF-1
activity (relative luciferase activity, 6%). This inhibition was
markedly reduced with each of the DAX-1 mutant vectors tested (W171X,
44%; 702delC, 90%; Y399X, 132%).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The clinical diagnosis of AHC is not always easily recognized. Boys who present in the neonatal period with salt-wasting and adrenal insufficiency are sometimes misdiagnosed with the more common disorder, 21-hydroxylase deficiency (congenital adrenal hyperplasia), although the adrenal steroid profiles of these conditions are quite different. In AHC, 17-hydroxyprogesterone levels are low, whereas they are increased in congenital adrenal hyperplasia. Distinguishing these two disorders is important because they differ in their clinical course, steroid management, and genetic counseling. The recessive form of AHC should also be considered as a cause of primary adrenal insufficiency in infancy. It has a distinct miniature adult adrenal morphology, characterized by small glands with a permanent cortical zone but a diminished fetal zone (2). The genetic basis of the recessive form of AHC is unknown. Finally, adrenal gland hypoplasia may also occur in neonates with congenital defects of the hypothalamus or pituitary, leading to ACTH deficiency. This can be differentiated from the primary adrenal failure seen in X-linked AHC by relevant measurements of electrolytes, mineralocorticoids, glucocorticoids, and ACTH, and by the phenotypic features (e.g. anencephaly) present in a subset of these children.
Some of our patients who presented in childhood were diagnosed with Addison’s disease. However, the failure to enter puberty, and the family history of adrenal insufficiency, prompted reconsideration of the initial diagnosis and genetic investigation for X-linked AHC. In fact, when a strong family history suggests X-linked adrenal insufficiency, adrenoleukodystrophy should also be excluded, because it can occasionally occur as adrenal insufficiency without associated neurological features (33). Serum very long-chain fatty acids will be elevated in adrenoleukodystrophy but normal in AHC.
Variability in the presentation of patients with AHC raises the issue
of whether the type of DAX-1 mutation predicts the severity
of the disorder. That is, is there a relationship between genotype and
phenotype? In the absence of detailed or standardized biochemical and
physiological data in many cases, age at diagnosis remains the most
accessible surrogate marker for assessing the severity of adrenal
dysfunction. When the age of diagnosis of AHC is summarized for
patients reported here and in other studies (6, 13, 14, 32, 34, 35, 36, 37, 38, 39, 40, 41, 42), an
apparent bimodal distribution emerges (Fig. 4). The majority of patients are
diagnosed within the first 2 months of life. Subsequently, few patients
are diagnosed until later in childhood, with similar numbers of
patients presenting between the ages of 2 to 9 yr.
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It is possible that the neonatal period is a particularly vulnerable
time for adrenal insufficiency because, in reported cases, many boys
present in severe salt-losing crises at this time (Fig. 4). For those
who do not, a more delayed and insidious presentation in childhood
seems to occur. There are several factors that could explain this. The
normal aldosterone secretion rate, although fairly constant
throughout life, is much higher in infancy when related to body
surface area (43, 44). This finding suggests that there is normally a
greater requirement for mineralocorticoids in early life. Increased
mineralocorticoid requirements could reflect relatively low sodium
intake and limited access to fluids at this age, the tendency to
urinary sodium loss caused by higher concentrations of atrial
natriuretic peptide (45), and the relative insensitivity of the
immature kidney to mineralocorticoid action (46). Certain other
clinical conditions associated with salt loss (such as 21-hydroxylase
deficiency and aldosterone synthase deficiency) show an improvement in
salt retention as patients get older (46, 47, 48). Thus, if patients with
AHC survive the neonatal period, they may become less susceptible to
adrenal crisis until faced with severe illness or another environmental
stress later in life.
The DAX-1 mutations described in our study resulted in
abnormal DAX-1 proteins that either completely lacked or had truncated
ligand-binding domains. Most reported DAX-1 mutations
reported so far have arisen from gene deletions or premature stop
codons that cause a loss of the carboxy-terminal region (6, 13, 14, 32, 34, 35, 36, 38, 39, 41, 42, 49, 50). The exceptions include nine different
missense mutations (Fig. 2), located at amino acids 267 and 269 (13, 32), 291 (39), 300 (37), 377 (32), 382 (39), 385, 425 (32), and 440
(40). These missense mutations are particularly useful for identifying
important functional domains in DAX-1. In a proposed three-dimensional
model of DAX-1, residue 382 was suggested to maintain helix-to-helix
contact through a buried salt bridge (17). The location of a missense
mutation in the extreme carboxy-terminus of DAX-1 (e.g.
N440I) is consistent with the observation that various mutations that
truncate this region of DAX-1 are sufficient to cause AHC.
Wild-type DAX-1 was shown recently to inhibit the transcriptional effects of SF-1 (27). DAX-1 has also been shown to suppress expression of the SF-1-regulated steroidogenic acute regulatory protein promoter (17). Deletion of the carboxy-terminal end of DAX-1 reduces its ability to silence gene expression (17, 27, 29). Therefore, AHC appears correlated with loss of DAX-1 transcriptional repression by disruption of its silencing domain function. We used these features of DAX-1 to test whether the W171X, 702delC, and Y399X mutations reported here altered DAX-1 function. Each one of these mutations was found to eliminate the ability of DAX-1 to inhibit SF-1-mediated transcription. These types of reporter gene assays may be useful to assess the functional effects of DAX-1 mutations.
In summary, we identified six mutations in the DAX-1 gene causing AHC with a spectrum of clinical presentations. Mutational analysis of the DAX-1 gene was useful for definitive diagnosis of the patient as well as for genetic counseling in families. These mutations were shown to eliminate the ability of DAX-1 to inhibit SF-1-mediated transcription. Animal models of Dax-1 mutations and overexpression (11), in conjunction with longitudinal studies in humans, will be useful to further define the functional role of DAX-1.
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Acknowledgments |
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Footnotes |
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2 These authors contributed equally to this work.
3 Current address: Department of Medicine, The Albert Einstein
Cancer Center, Albert Einstein College of Medicine, Bronx, NY
10461.
Received June 4, 1998.
Revised October 5, 1998.
Accepted October 21, 1998.
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X-Linked Adrenal Hypoplasia Congenita: A Mutation in DAX1Expands the Phenotypic Spectrum in Males and Females J. Clin. Endocrinol. Metab., December 1, 1999; 84(12): 4501 - 4509. [Abstract] [Full Text]
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