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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 6 2287-2292
Copyright © 2000 by The Endocrine Society

Original Studies

Identification of a New Missense Mutation (Gly95Glu) in a Highly Conserved Codon within the High-Mobility Group Box of the Sex-Determining Region Y Gene: Report on a 46,XY Female with Gonadal Dysgenesis and Yolk-Sac Tumor

A. Schäffler, N. Barth, K. Winkler, B. Zietz, P. Rümmele, R. Knüchel, J. Schölmerich and K.-D. Palitzsch

Department of Internal Medicine I (A.S., N.B., K.W., B.Z., J.S., K.-D.P.), Institute of Pathology (P.R., R.K.), University of Regensburg, D-93053 Regensburg, Germany

Address correspondence and requests for reprints to: A. Schäffler, Department of Internal Medicine I, University of Regensburg, D-93053 Regensburg, Germany. E-mail: andreas.schaeffler{at}klinik.uni-regensburg.de


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Leydig cells and Sertoli cells of the testes produce hormones that cause male differentiation, if receptors are present. The Y chromosomal SRY gene (sex determining Region Y gene) acts as TDF and is required for regular male sex determination. SRY represents a transcription factor belonging to the superfamily of genes sharing the HMG-box motif (high-mobility group-box), which acts as DNA binding region. Here, we describe a nonmosaic XY sex-reversed female with pure gonadal dysgenesis (46,XY karyotype, completely female external genitalia, normal Müllerian ducts, absence of Wolffian ducts, streak gonads) who harbored a yolk-sac tumor and was referred for the assessment of primary amenorrhea. Using genomic PCR analysis, a 423-bp PCR product, encompassing the HMG-box of the SRY gene, was amplified from the proposita, her father, and her three brothers, whereas no band was visible in the patient’s mother and her three sisters. The PCR products were sequenced for mutations subsequently. A new de novo missense mutation within the HMG-box of the SRY gene was discovered in the proposita. A G is replaced by an A in codon 95 at position +284, resulting in the replacement of the nonpolar aminoacid glycine by the polar amino acid glutamate. The glycine at codon 95 is highly conserved between the family of HMG-box proteins and between species. This point mutation has not been described earlier and brings the total number of SRY mutations described so far to 36, each mutation being unique. This mutation was not detected in the patient’s father and her male siblings. The present data provide further evidence to support the functional importance of the putative DNA binding activity of the SRY HMG-box domain.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
IN THE ABSENCE of Y chromosomal-derived information, ovaries are formed, resulting in a female phenotype. The essential step in normal male sexual differentiation occurs during the 5th-6th week of gestation and requires Y chromosomal-derived information.

Testes determination requires the activation of a cascade of both autosomal and Y chromosomal genes. Originally, the putative gene on the Y chromosome that causes the bipotential gonad to develop as testis was named testis-determining factor (TDF). After TDF was mapped to the short arm of the Y chromosome (1, 2), the candidate region was subsequently narrowed down to a 35-kb interval on the Y chromosome adjacent to the pseudoautosomal boundary (3). Analysis of this region revealed a Y chromosomal-specific sequence, named SRY (sex-determining region Y gene) (3). The demonstration, that mice transgenic for Sry developed into sex-reversed males despite an XX karyotype (4), provided the final confirmation of SRY being the TDF that directs the undifferentiated gonad into a testis (for review, see Ref. 5).

SRY is generally assumed to be responsible for triggering Sertoli cell development (5). The ability of the SRY protein to bind and bend target DNA seems to be critical to its function. Although there exist a number of consensus binding sites with the A/TAACAAT motif of SRY within a number of genes as Wilm’s tumor gene-1, MIS (Müllerian inhibiting substance), fos-related-antigen-1, or P450 aromatase, there is no convincing proof that SRY directly regulates these genes (6, 7, 8, 9, 10). In contrast, SRY was suggested to represent a transcriptional master regulator switching on genes located in the downstream regulated pathway of sex differentiation. When put under the control of a heterologous promoter, SRY can activate transcription of a reporter construct containing multiple copies of the AACAAT motif. Thus, one can speculate that SRY acts as transcriptional activator (11). SRY protein can also bind the MIS promoter in gel retardation assay and thus may initiate MIS transcription (12). These data were confirmed by Haqq et al. (13). In addition, SRY also enhances the transcription of fos-related antigen-1 in cotransfection experiments (10). In contrast, Graves (14) proposed that SRY only functions indirectly, by inhibiting SOX-3 and permitting SOX-9 (SRY-like HMG box genes) to enact its testis-determining role.

Mutations in the SRY gene are among the known cases of XY sex reversal, and an increasing variety of unique mutations within this gene have been reported in patients with gonadal dysgenesis/XY sex reversal (Tables 1Go and 2Go). These patients are, in general, normal 46,XY females with complete gonadal dysgenesis.


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  		Table 1. Nucleotide substitutions (missense/nonsense) in the HMG box of the human gene for SRY

 

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  		Table 2. Deletions, insertions, and substitutions in the human gene for SRY

 
We report on a mutation scan of the HMG box domain of the SRY gene in a 46,XY female patient with gonadal dysgenesis and yolk-sac tumor.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Extraction of genomic DNA and PCR analysis

DNA was obtained from a phenotypic female 46,XY individual, her parents, three brothers, and three sisters. Genomic DNA was extracted from blood of each subject, following standard procedures, using the QIAamp DNA Blood Kit (QIAGEN, Hilden, Germany). All participating individuals were informed about the aim of the study and gave informed consent. The investigation was conducted according to the guidelines expressed in the Declaration of Helsinki. Genomic PCR was performed following standard procedures using the Taq PCR Core Kit (QIAGEN). The HMG box of the human SRY gene was amplified using the upstream primer SRY-up (5'-AGAATATTCCCGCTCTCCGG-3') complementary to nucleotides +65 bp to +84 bp and the downstream primer SRY-down (5'-ACAACCTGTTGTCCAGTTGCAC-3') corresponding to nucleotides +471 bp to +490 bp relative to the ATG start codon [accession numbers L10102 (15) and AAA16878 (16)]. Using these primers, a 423-bp PCR product, encompassing the HMG box of SRY, was amplified from genomic DNA.

Sequencing

PCR products were purified, and both strands were sequenced directly using the ABI Prism 310 Capillary Sequencer, (ABI, PE Applied Biosystems, Foster City, CA).


   Results
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 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Case report

We report on a 33-yr-old phenotypic female patient, who was referred for the assessment of primary amenorrhea and infertility. The patient is the second child born to healthy unrelated parents.

Patients history

Besides the primary amenorrhea, her childhood development had been quite normal (delayed breast tissue development at the age of 16 and sparse pubic hair development at the age of 17), and she had not experienced any serious illnesses. At age 26, she was submitted to laparatomy because of severe abdominal pain and a bulky tumor detected by abdominal computed tomography scan. During laparatomy, a 13 x 12 cm, obviously retroperitoneal-located tumor infiltrating the mesentery, cava vein, aorta, and duodenum, was removed. Right-sided hemicolectomy, resection of aorta and inferior cava vein, aortoiliacal prothesis, and excision of duodenal wall was performed. Metastases of the liver and the spleen were also present. Histological examination revealed a yolk-sac tumor (pT4) with chorionic giant cells, positive for {alpha}-1-fetoprotein and keratin and negative for ß-HCG (Fig. 1Go). Surgery was followed by chemotherapy using cisplatin, etoposide, and bleomycine. At that time, no assessment of the primary amenorrhea had been performed. No relapse of the tumor has been registrated during follow-up.



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  		Figure 1. Histological section of yolk sac tumor in a 46,XY phenotypic female patient. A, Microcystic pattern and endodermal sinus pattern of yolk sac tumor (HE; magnification, x100); B, endodermal sinus pattern of yolk sac tumor (HE; magnification, x200).

 
Physical examination

The physical examination revealed an apparently normal, but obese, female with a weight of 85 kg and a height of 175 cm. Although the external genitals were unambiguously female, they were infantile and with no hypertrophy of the clitoris. Vagina and cervix were present. Mammary development was at Tanner stage B3. Axillary and pubic hair was sparse but of typical female habitus. No signs of virilization were noticeable. There was no evidence of Turner stigmata, short stature, or mental retardation. At laparatomy, the patient had bilateral streak gonads, well-formed Müllerian structures, including normal fallopian tubes and a hypoplastic uterus. No Wolffian structures were observed.

Biochemical findings

Laboratory examination revealed that the amenorrhea was caused by ovarian failure. Elevated levels for FSH (88.3 IU/L; range, 1–12 IU/L) and LH (31.8 IU/L; range, 0.6–19 IU/L), together with low levels for estradiol (9.0 pmol/L; range, 100–610 pmol/L) were observed. There was no elevation of androgen levels. Total testosterone (0.37 µg/L; range, 0.11–1.1 µg/L) and free testosterone (0.3 ng/L; range, 0.7–3.6 ng/L) were low, and levels for androstendion, DHEA-S, and progesterone were normal. Whereas {alpha}-1 fetoprotein was highly elevated (>350 U/mL; range < 7 IU/mL), ß-HCG was measured within the normal range.

Karyotype analysis

Repeated chromosome analysis from leukocyte cultures consistently showed a nonmosaic 46,XY karyotype. The lack of evidence of 45,X0/46,XY and other forms of mosaicism served to exclude the more common forms of gonadal dysgenesis. Streak gonads, the presence of Müllerian ducts, the absence of Wollfian ducts, and female external genitals were documented and regarded as sufficient to exclude the diagnosis of androgen insensitivity and testicular regression syndromes.

The 46,XY female patient in this study was referred for analysis of the SRY gene, on the basis of cytogenetic examination showing a nonmosaic 46,XY karyotype and careful clinical examination indicating typical features of pure gonadal dysgenesis.

Genetic Analysis of the SRY gene

Using the above mentioned primer combination, the HMG-box of the SRY gene was successfully amplified in the proposita (Fig. 2Go, lane 3), her father (Fig. 2Go, lane 1), and her three brothers (Fig. 2Go, lanes 4–6). As expected, no band was visible in the patient’s mother (Fig. 2Go, lane 2) and her three sisters (Fig. 2Go, lanes 7–9), because of the absence of the Y chromosome.



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  		Figure 2. Genomic PCR analysis of the HMG box of the human SRY gene. A 423-bp PCR product encompassing the HMG-box of the human SRY gene was amplified. All family members of the phenotypic female 46,XY patient were investigated. {lambda} = DNA molecular weight marker; 1 = father; 2 = mother; 3 = proposita; 4 = brother-1; 5 = brother-2; 6 = brother-3; 7 = sister-1; 8 = sister-2; 9 = sister-3.

 
The PCR products of the proposita, her father, and her brothers were sequenced, to scan for mutations within the HMG-box. The proposita was demonstrated to carry a G->A point mutation at position +284 in codon 95 (Fig. 3Go), whereas the father and all three brothers were proven to have the wild-type sequence. The point mutation causes the replacement (Fig. 4Go) of the nonpolar amino acid glycine (GGA) by the polar amino acid glutamate (GAA) in helix II of the HMG-box. As shown in Fig. 4Go, codon 95 is highly conserved between the HMG-box containing genes, and between species. As demonstrated by database analysis, homology search, and review of the literature, this mutation was not described earlier and thus seems to be unique.



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  		Figure 3. Identification of a new de novo missense mutation (Gly95Glu, GGA->GAA) in the HMG box of the human SRY gene in a phenotypic female 46,XY patient. A, Electropherogram of the wild-type PCR fragment from the patient’s healthy male 46,XY father; B, electropherogram of the PCR fragment from the phenotypic female 46,XY patient.

 


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  		Figure 4. The amino acid substitution Gly95Glu in the HMG domain of SRY occurs at the highly conserved glycine in codon 95. Amino acid sequences of members of the subfamily (28 36 ) of sequence-specific HMG-domain proteins are compared (according to Ref. 37). The regions corresponding to the three alpha helices identified in the structure of the B-domain in rat HMG1, rHMG1-B (35 ), are indicated by brackets.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Normal male sex determination in mammals is targeted by the SRY gene on the Y chromosome. Timing and expression of SRY are exquisitely regulated and probably must reach a threshold required for testis formation (5, 17). The TDF is encoded by the SRY gene and represents a transcription factor with a highly conserved DNA binding domain belonging to the high-mobility (HMG)-box family of DNA binding proteins. By molecular investigation of sex-reversed male XX patients with testes carrying minute portions of genetic Y material translocated to the X chromosomes, TDF was mapped to human Y chromosome (3, 18) and defined later (3) to a 35-kb region of Y-specific DNA near the pseudoautosomal boundary. Sinclair et al. (3) identified a gene within this region that they named SRY (sex-determining region Y). The functional SRY transcript seems to be a conditio sine qua non for a normal fertile male development of the testis. Studies in mice support the testicular determining function of SRY. If Sry was deleted from a mutant Y chromosome, it was no longer sex determining (19). If the Sry gene is introduced into mouse ova, XX sex-reversed transgenic mice can be produced (20). This is compelling evidence that SRY is the TDF. However, there exists a case report of two male 46XX individuals found to be negative for the SRY gene sequence, suggesting that an inherited loss-of-function mutation in an unknown gene, that is involved in the sex-determining process, can induce normal male sexual differentiation (21).

The SRY transcript acts (for review, see Ref. 5) as a transcription factor, regulating downstream autosomal genes (22) in a sequential fashion, to induce Sertoli cell development in the bipotential primordial gonad. Then, differentiation of Sertoli cells occurs and leads to further testicular development, including differentiation of testosterone-producing Leydig cells. By the secretion of testosterone and antimüllerian hormone and the effects of these hormones on specific receptors, normal male sex differentiation is achieved.

The gene structure and promoter region of SRY was elucidated by Su et al. (15), Behlke et al. (16), and Clepet et al. (23) in 1993. The entire SRY protein is encoded by a single exon (16) and represents a DNA-binding protein that affects the transcription of the sex-determining gene(s) in a trans manner (3). The transcription in human adult testis involves multiple start sites (23), but the predominant SRY transcript encompasses the open reading frame for a 204-amino-acid protein carrying a 79-amino-acid HMG-box within the midregion of the molecule (23). The SRY protein acts with DNA of target genes in a sequence-specific manner via its HMG-box motif (10, 11, 12, 13, 24, 25, 26, 27, 28, 29). The HMG domain of the SRY gene represents an evolutionary highly conserved motif found in chromosomal nonhistone HMG proteins, like HMG-1, and in a number of transcription factors (13, 17, 18, 19) as T cell factor-1 and lymphoid enhancer factor-1. In vitro oligonucleotide experiments suggested the DNA target sequence A/TAACAAT as the consensus binding site for the SRY protein (20). In addition, the SRY protein also produces a dramatic bend in the target DNA, a mechanism that possibly brings other regulatory elements into juxtaposition (30).

Mutations in the SRY gene result in XY females with gonadal dysgenesis. Translocations of this gene sequence to X chromosomes give rise to XX males. Because no polymorphisms have been detected in the SRY gene among 50 normal XY males (17), mutations in the SRY gene seem to occur almost always de novo and mostly lead to 46,XY unambiguous females with no testicular differentiation. There are only four reports of familial 46,XY complete gonadal dysgenesis associated with SRY gene mutations affecting the HMG box. Variable penetrance of the mutation and paternal gonadal mosaicism are possible explanations for this phenomenon (17, 31).

Postzygotic mutations in the SRY gene are extremely rare (32); and in these cases, only gonadal DNA but not leukocyte DNA, is mutated (33). To date, 30 nucleotide substitutions, 1 missense deletion, 1 missense insertion, 2 frame shift deletions, and 1 regulatory substitution have been reported in patients with gonadal dysgenesis. Tables 1Go and 2Go summarize all mutations of the human SRY gene that have been detected up to now.

In this article, we describe a newly discovered point mutation within the HMG-box motif of SRY in a German 46,XY female with gonadal dysgenesis. This mutation resulted in a change from the nonpolar GGA to the polar GAA that lies within the putative DNA binding motif. The mutation seems to have occurred de novo, because the patients father and brothers showed wild-type sequence. However, because of the possibility that the father may represent a germ cell mosaic, we can not prove this hypothesis.

The HMG domain is composed of three {alpha} helices and adopts an L shape (34, 35). The glutamate for glycine exchange at codon 95 occurs within helix II, introducing a polar charged for a nonpolar residue. This may have effects on the helix itself or impair DNA binding. As demonstrated by sequence comparison (Fig. 4Go), the glycine at codon 95 is strictly conserved between the SRY genes of all species studied to date (36, 37, 38), suggesting that this amino acid is essential for the function of the HMG-box in the context of the SRY protein. These results strongly suggest that this mutation in the SRY gene is unique and is associated with gonadal dysgenesis in the 46,XY female.

Received October 27, 1999.

Revised February 20, 2000.

Accepted March 11, 2000.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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