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Three Novel Mutations and a De Novo Deletion Mutation of the DAX-1 Gene in Patients with X-Linked Adrenal Hypoplasia Congenita

Department of Pediatrics (J.N., S.A., T.T., N.S., M.M., K.F.), Hokkaido University School of Medicine, Sapporo 060; Igarashi Pediatric Clinic (Y.I.), Sendai; Department of Neonatology (S.K.), Osaka City General Hospital, Osaka; Department of Pediatrics (J.S.), Fukushima Prefectural Medical Collage, Fukushima, Japan

Address correspondence and requests for reprints to: Kenji Fujieda, Department of Pediatrics, Hokkaido University School of Medicine, North-15, West-7, Kitaku, Sapporo 060, Japan. E-mail: ken-fuji{at}med.hokudai.ac.jp

	Abstract

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The DAX-1 [DSS (dosage sensitive sex)-AHC critical region on the X, gene 1] gene is responsible for X-linked adrenal hypoplasia congenita (AHC). However, DAX-1 protein structure-function relationships are not well understood. Identification of missense mutations may help to reveal these relationships. We analyzed the DAX-1 gene from seven patients in six kindreds with X-linked AHC and identified one frameshift mutation, two missense mutations, and three deletion mutations. Case 1 had a 388delAG frameshift mutation, inducing a premature stop codon at position 70. Case 2 had a missense mutation, Lys382Asn, which encodes an asparagine (Asn) for lysine (Lys) at position 382. Sibling cases of 3-1 and 3-2 had a missense mutation of Trp291Cys, which encodes a substitution of cysteine (Cys) for tryptophan (Try) at position 291. The tryptophan (Trp) at position 291 and lysine (Lys) at position 382 in human DAX-1 protein are highly conserved among other related orphan nuclear receptor superfamily members. Cases 4, 5, and 6 showed deletion mutation. In case 6, a de novo deletion mutation was revealed by both southern hybridization and polymerase chain reaction (PCR) of a GGAA tetranucleotide tandem repeat. These findings suggest that: 1) Trp at position 291 and Lys at position 382, located in the C-terminal presumptive ligand binding domain, are important to the functional role of the DAX-1 protein in adrenal embryogenesis and/or in hypothalamic-pituitary activity; and 2) molecular analysis of the DAX-1 gene may help genetic counseling, even in cases with deletion mutation, because a detection of de novo deletion may exclude another affected or carrier child.

	Introduction

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X-LINKED ADRENAL hypoplasia congenita (AHC) is a rare congenital adrenal disorder characterized by severe adrenal insufficiency. This disorder often manifests salt-losing adrenal insufficiency during the neonatal period and requires intensive medical care (1, 2, 3, 4, 5, 6, 7, 8, 9, 10). The DAX-1 [DSS (dosage-sensitive sex)-AHC critical region on the X, gene 1] gene was identified as responsible for both X-linked AHC and hypogonadotropic hypogonadism (HH) (11, 12). The DAX-1 gene encodes the presumptive transcription factor and is classified as an orphan nuclear receptor (11, 12). The DAX-1 protein is a 470 amino acid polypeptide, with its coding sequence split by a single intron of about 3 kb. The C-terminal half of the protein has high homology with the ligand-binding domain (domain E) of the nuclear hormone receptor gene superfamily, especially with the E domain of the retinoid X receptor (RXR) and the orphan receptor (EAR-2, seven-up, COUP, ARP-1) subfamilies. The N-terminal portion contains 4 incomplete repeats of a new structural motif encoding a DNA-binding function, and the DAX-1 protein is reported to bind retinoic acid (RA) responsive elements and downregulate RA receptor-mediated transcriptional activation (11). The C-terminal half domain of the DAX-1 protein is similar to the ligand-binding domain (E-domain) of the nuclear hormone receptor superfamily (11, 13, 14). The DAX-1 gene was expressed in adult testis and adult adrenal tissue and has an important role in development of these tissues (11). However, the structure and function of the DAX-1 protein remains to be demonstrated. Molecular analysis of the DAX-1 gene in patients with X-linked AHC gives insight into the structure and function of the DAX-1 protein. Over 20 different mutations have now been identified (12, 15, 16, 17, 18, 19, 20, 21). No relationship between the onset of disorder and the site of mutation has been demonstrated. Furthermore, the C-terminus of this protein plays an important role in its function.

In the present study, we analyzed the DAX-1 gene in seven patients from six kindreds and identified one novel frameshift mutation, two novel missense mutations, and a de novo deletion mutation of the DAX-1 gene. We discussed the functional significance of the mutated amino acids.

	Subjects and Methods

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Subjects (Tables 1 and 2)

Clinical and laboratory findings are shown in Tables 1 and 2. The onsets of the disorder in all cases, except cases 3-1 and 3-2, were during their neonatal period. Cases 3-1 and 3-2 manifested adrenal insufficiency at the ages of 2 yr and 3 yr, respectively. The initial symptoms of all cases except cases 3-1 and 3-2 were failure to thrive, generalized pigmentation, poor feeding, or vomiting. The initial symptom of cases 3-1 and 3-2 was only generalized pigmentation. In addition, cases 4 and 5 had also mental retardation. Laboratory findings of all cases at diagnosis showed hyponatremia, hyperkalemia, increased levels of plasma ACTH and plasma renin activity (PRA), or impaired serum cortisol response to the administration of ACTH. However, in cases 3-1 and 3-2, levels of serum potassium and plasma ACTH were modestly elevated. Case 1 is now 26 yr old. He is 179.3 cm tall (+1.5 SD for the mean of normal Japanese male) with 67.5 kg of weight (+0.5 SD for the mean of normal Japanese male). His external genitalia is Tanner stage 1 and bone age estimated by the Greulich and Pyle method is 14 yr old. Case 4 is now 15 yr old with Tanner stage 1 genitalia. His serum testosterone level is less than 5.0 ng/dL. However, the administration of human chorionic gonadotropin (hCG) at a dose of 4000 IU for 4 days increased serum testosterone to 186.1 ng/dL. In both cases, serum LH and FSH values were not measured. Other cases are in the prepubertal age. Informed consent was obtained from each family. This study was approved by the Regional Committee for Medical Research Ethics.

Genomic DNA was isolated from peripheral lymphocytes. PCR was performed using primer pairs specific for the DAX-1 gene. PCR amplification was performed as described previously (18). Direct sequencing of amplified PCR products was determined from both strands using an automated sequencer (ABI PRISM 310 Genetic Analyzer, Applied Biosystems, Foster City, CA). The mutations detected were confirmed in mothers and other family members by sequencing their genomic DNA partially. Furthermore, to confirm mutations detected, sequence-specific oligonucleotide hybridization was performed. In brief, genomic DNA from each case was amplified by PCR using primer 1 and 2 (18) for the 388delAG frameshift mutation, primer 7 and 10 (18) for the Lys382Asn mutation, or primer 7 and 8 (18) for the Trp291Cys mutation. After amplification, each PCR product was electrophoresed in 2% agarose gel and blotted onto nitrocellulose filter. Each filter was hybridized in solution containing 6 x SSC, 5 x Denhardt’s solution, 0.05% sodium pyrophosphate, 0.5% SDS, and 100 µg/mL salmon sperm DNA with sequence-specific ³²P-end labeled 21-mer oligonucleotide at 42C for 20 h. Each oligonucleotide was labeled with ³²P-ATP as described elsewhere (22). For the 388delAG frameshift mutation, wild and mutant type oligonucleotides were 5'-GTG GGC AGA GAG GGG CTG CTG-3' (nucleotides 379-399) (388Wild) and 5'-GTG GGC AGA GGG GCT GCT GGG-3' (388delAG), respectively. For the Lys382Asn mutation, wild and mutant type oligonucleotides were 5'-GCC TAC CTC AAG GGG ACC GTG-3' (nucleotides 1369–1389) (Lys382) and 5'-GCC TAC CTC AAT GGG ACC GTG-3' (Asn382), respectively. For the Trp291Cys mutation, wild and mutant type oligonucleotides were 5'-CGC AAC TGC TGG GCG TCC CTG-3' (nucleotides 1096-1117) (Trp291) and 5'-CGC AAC TGC TGC GCG TCC CTG-3' (Cys291), respectively. The positions of all oligonucleotides were in accordance with those previously described (11). After hybridization, each filter was washed at room temperature for 10 min 3 times, and at 65–70C for 5 min once in solution containing 6 x SSC and 0.05% sodium pyrophosphate and exposed to autoradiography film for 1–2 h at -80C with an intensifying screen.

Southern hybridization of the DAX-1 gene

In each case where DAX-1 gene could not be amplified by PCR, Southern blotting was performed as described elsewhere (22). In brief, genomic DNA (10 µg) was digested with EcoRI, electrophoresed in 0.8% agarose gel, and blotted onto a nitrocellulose filter. The filters were probed with the DAX-1 cDNA and human insulin receptor (IR) complementary DNA (cDNA). The DAX-1 cDNA (nucleotides 889-1708) was obtained by reverse transcriptase-PCR using the DAX-1 gene-specific primer pairs [primer 7 and 12 (18)] from messenger RNA of human adrenal adenoma in a patient with Cushing syndrome. The human insulin receptor (IR) cDNA (p13-1), which was about 1.0 kb pairs of the 5'-portion of human IR cDNA cloned into EcoRI site of a pUC 12 vector was provided by I. Smith (Genentech, Inc., San Francisco, CA). Intensities of bands detected were measured by NIH Image (NIH computer center shareware).

PCR of a GGAA tetra-nucleotide tandem repeat

The DAX-1 gene has two potentially polymorphic short tandem repeats (17). One of them, the GGAA tetra-nucleotide tandem repeat [(GGAA)₆GGAAA(GGAA)₅GGAAAGGAAGGAAA(GGAA)₁₀], is located in the promoter region of the DAX-1 gene (nucleotides -1492 ~ -1395) (17). To confirm double dosage of the DAX-1 gene from the mother of case 6, we performed PCR of the GGAA tetra-nucleotide tandem repeat from family members of case 6, normal male and female controls. PCR was performed with slight modification in accordance with the procedure previously described (17). In brief, the 50-µL PCR reaction contained 500 ng genomic DNA, primer 15 and 3140 (50 pmol/L each) (17), 20 nmol/L deoxynucleotide triphosphate, 0.1 µL -³²P-deoxycytidine triphosphate (300 Ci/mmol and 10 mCi/mL; Amersham, Arlington Heights, IL), two units of Taq DNA polymerase (Perkin Elmer, Foster City, CA) and the PCR buffer contained 10 mmol/L Tris-HCl (pH 8.8), 50 mmol/L KCl, 1.5 mmol/L MgCl₂, and 0.1% gelatin. The PCR condition for amplification of this fragment was 1.0 min denaturation at 94C, 1.0 min annealing at 55C, and 1.0 min extension at 72C for 32 cycles. A 3-µL aliquot of the PCR reaction was mixed with 9 µL of the stop solution (95% formamide, 10 mmol/L EDTA, pH 8.0, 0.01% xylene cyanol) and denatured for 5 min at 94C. Then, 4-µL aliquots of the mixtures were loaded on 6% polyacrilamide/8.3 mol/L urea gel. Electrophoresis was performed at 1200 volts for 5 h. The gel was dried before being exposed to autoradiography film for 2 h at -80C with an intensifying screen.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
PCR-direct sequencing of the DAX-1 gene

In 4 patients from 3 kindreds, one frameshift mutation (388delAG) and two missense mutations (Lys382Asn and Trp291Cys) were identified. In case 1, the 388delAG mutation had a deletion of two bases (AG) at nucleotides 388 and 389, inducing a frameshift and a premature stop codon at position 70 (Fig. 1A). In case 2, a missense mutation, Lys382Asn, was due to a transversion of G to T at nucleotide 1380, encoding an asparagine (Asn) for lysine (Lys) at position 382 (Fig. 2A). The mother of case 2 was heterozygous for the Lys382Asn mutation. The sister of case 2 did not have any mutation (data not shown). Sibling cases of 3-1 and 3-2 had missense mutations of Trp291Cys, due to a transversion of G to C at nucleotide 1107, which encodes a substitution of cysteine (Cys) for tryptophan (Try) at position 291 (Fig. 3A). Their mother was heterozygote for the mutation (data not shown). The Lys382Asn and Trp291Cys mutations were not detected in 50 normal controls. Sequence-specific oligonucleotide hybridization allowed the demonstration of the cosegregation of these mutations with X-linked AHC (Figs. 1B, 2B, 3B).

View larger version (15K): [in this window] [in a new window]   Figure 1. A, Partial nucleotide sequence of the DAX-1 gene of case 1. After amplification using primers 1 and 2 (18) and purification by electrophoresis on Nusieve low melting agarose gel (FMC BioProducts, Rockland, ME), the PCR-amplified product was directly sequenced, as described in Subjects and Methods. B, Sequence-specific oligonucleotide hybridization of case 1 (lane 1), normal male (lane 2), and normal female (lane 3). PCR of genomic DNA from each case and hybridization with wild type or mutant type oligonucleotide were performed, as described in Subjects and Methods. For the 388del AG frameshift mutation, wild type and mutant type oligonucleotides were 5'-GTG GGC AGA GAG GGG CTG CTG-3' (nucleotides 379-399) (388Wild) and 5'-GTG GGC AGA GGG GCT GCT GGG-3' (388delAG), respectively.

View larger version (20K): [in this window] [in a new window]   Figure 2. A, Partial nucleotide sequence of the DAX-1 gene of case 2. After amplification using primers 7 and 10 (18) and purification by electrophoresis on Nusieve low melting agarose gel, the PCR-amplified product was directly sequenced, as described in Subjects and Methods. B, Sequence-specific oligonucleotide hybridization of case 2 (lane 1), his mother (lane 2), and sister (lane 3). PCR of genomic DNA from each case and hybridization with wild type or mutant type oligonucleotide were performed, as described in Subjects and Methods. For the Lys382Asn mutation, wild type and mutant type oligonucleotides were 5'-GCC TAC CTC AAG GGG ACC GTG-3' (nucleotides 1369–1389) (Lys382) and 5'-GCC TAC CTC AAT GGG ACC GTG-3' (Asn382), respectively.

View larger version (21K): [in this window] [in a new window]   Figure 3. A, Partial nucleotide sequence of the DAX-1 gene of case 3-1. After amplification using primers 7 and 8 (18) and purification by electrophoresis on Nusieve low melting agarose gel, the PCR-amplified product was directly sequenced, as described in Subjects and Methods. B, Sequence-specific oligonucleotide hybridization of case 3-1 (lane 1), case 3-2 (lane 2), his father (lane 3), mother (lane 4) and sister (lane 5). PCR of genomic DNA from each case and hybridization with wild type or mutant type oligonucleotide were performed, as described in Subjects and Methods. For the Trp291Cys mutation, wild type and mutant type oligonucleotides were 5'-CGC AAC TGC TGG GCG TCC CTG-3' (nucleotides 1096-1117) (Trp291) and 5'-CGC AAC TGC TGC GCG TCC CTG-3' (Cys291), respectively.

In three cases of patients 4, 5, and 6, the DAX-1 gene could not be amplified by PCR. To identify a deletion mutation of the DAX-1 gene in cases of 4, 5, and 6, we performed a Southern hybridization. Deletion mutations of the DAX-1 gene were detected in these cases (Fig. 4A, lane 1, 5, and 7). The mother of case 6 had double dosage of the DAX-1 gene of the proband. Furthermore, Southern hybridization of the same filter probed with human IR cDNA (p13-1) demonstrated the same intensity of the human IR gene in the proband and his mother (Fig. 4B). Ratios of intensity of bands of the DAX-1 and human IR genes measured by NIH Image were 1.30 in the mother and 0.70 in the father, respectively. If the mother of case 6 is a carrier of deletion mutation of the DAX-1 gene, she should have the same dosage of the DAX-1 gene as the father of case 6. Furthermore, PCR of the GGAA tetra-nucleotide tandem repeat from family members of case 6 detected no band in case 6, two bands in the mother, and one band in younger brother of case 6 (Fig. 5, lane 4, 6, and 7, respectively). These data suggest that deletion mutation of the DAX-1 gene in case 6 occurred in de novo, indicating that his mother is not a carrier of this disorder.

View larger version (64K): [in this window] [in a new window]   Figure 4. A, Southern hybridization of the DAX-1 gene from case 4-6. After being digested with restriction enzyme, EcoRI, genomic DNA (10 µg) was electrophoresed on 0.8% agarose gel and Southern hybridization was performed as described in Subjects and Methods. The filter was probed with the DAX-1 cDNA. Lanes 1, 2, 3, 4, 5, 6, 7, 8, and 9 represent case 4, normal female, normal male, father of case 5, case 5, mother of case 5, case 6, father of case 6, and mother of case 6, respectively. B, Southern hybridization of human insulin receptor (IR) gene from case 6 and his parents. Genomic DNA was isolated from peripheral lymphocytes of case 6 and his parents. After being digested with restriction enzyme, EcoRI, genomic DNA was electrophoresed on 0.8% agarose gel and Southern hybridization was performed as described in Subjects and Methods. The filter was probed with the human IR cDNA. Lanes 1, 2, and 3 represent case 6, his father, and mother, respectively.

View larger version (52K): [in this window] [in a new window]   Figure 5. PCR of a GGAA tetra-nucleotide tandem repeat from family members of case 6, normal male, and female controls. PCR was performed using primers 15 and 3140 (17) as described in Subjects and Methods. Lane 1–3 represent normal males. Lanes 4, 5, 6, 7 represent case 6, father of case 6, mother of case 6, and younger brother of case 6, respectively. Lanes 8–10 represent normal female.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

View larger version (24K): [in this window] [in a new window]   Figure 6. Mutations in the DAX-1 gene currently identified. Mutations underlined were discussed in the present study. Other mutations were cited from references (12, 15–21). Arrows indicate positions of localization of the premature stop codon caused by nonsense or frameshift mutations, missense or deletion mutations.

It is interesting to note that cases 4 and 5 with deletion mutations of the DAX-1 gene are mentally retarded. In the present study, we did not study the extent of the deletion in their genomic DNA. However, it has been recently reported that a gene responsible for X-linked mental retardation (MR) is located near AHC on the X chromosome (25, 26, 27, 28). Thus, it is conceivable that these patients also have a deletion encompassing a gene responsible for X-linked mental retardation. Detailed mapping of the deletions in these patients might allow more refined localization of the MR locus, such as has been recently carried by Billuart et al. (28).

In conclusion, we identified three novel mutations, including one frameshift, two missense mutations, and a de novo deletion of the DAX-1 gene. Tryptophan at position 291 and lysine at position 382, located in the C-terminal presumptive ligand binding domain, may play an important role for the biological actions of the DAX-1 protein, such as in adrenal embryogenesis and/or in hypothalamic-pituitary activity. The identification of a de novo deletion of the DAX-1 gene reinforces the importance of genetic counseling with family members of a patient with X-linked AHC and HH. A detection of de novo deletion may exclude another affected or carrier child.

Received March 7, 1997.

Revised July 9, 1997.

Accepted July 15, 1997.

	References

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