Mol. Hum. Reprod. Advance Access originally published online on May 21, 2004
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Molecular Human Reproduction, Vol. 10, No. 7, pp. 521-526, 2004
Molecular Human Reproduction vol. 10 no. 7 © European Society of Human Reproduction and Embryology 2004; all rights reserved
Two new novel point mutations localized upstream and downstream of the HMG box region of the SRY gene in three Indian 46,XY females with sex reversal and gonadal tumour formation
1Human Genetics Laboratory, Department of Biosciences, Jamia Millia Islamia, New Delhi-110 025, India 2CSIRO Health Sciences and Nutrition, Adelaide, Australia 3Division of Molecular Oncology, ICMR (ICPO), Maulana Azad Medical College Campus, Bhadur Shah Zafar Marg, New Delhi-110 002, India 4Division of Reproductive Health & Nutrition, Indian Council of Medical Research, Ansari Nagar, New Delhi, India 5Department of Obstetrics & Gynecology, Lok Nayak Jai Prakash Hospital & Associates, Maulana Azad Medical College Campus, Bhadur Shah Zafar Marg, New Delhi-110 002, India
6 To whom correspondence should be addressed at: Genome Stability Laboratory, CSIRO Health Sciences and Nutrition, Gate No. 13, Kintore Avenue, P.O.Box 10041, Adelaide BC, Adelaide 5000, Australia.; Email: varinderpal.dhillon{at}csiro.aucorresponding
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Abstract |
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The Y chromosome-specific gene SRY is one of the key genes involved in human sex determination. The SRY gene encodes a testis-specific transcription factor that plays a key role in sexual differentiation and development in males and is located on the distal region of the short arm of the Y chromosome. Mutations in SRY gene result in XY sex reversal and pure gonadal dysgenesis. SRY expression initiates a network of gene activity that transforms the undifferentiated gonad, genital ridge into testis. Mutations in the SRY gene have been considered to account for only 10–15% of 46,XY gonadal dysgenesis cases, whereas the majority of the remaining cases may have mutation(s) in the SRY regulatory elements or other genes involved in the sex differentiation pathway. Patients both with gonadal dysgenesis and Y-chromosome presence are at high risk of developing gonadoblastoma. Using PCR, single strand conformational polymorphism (SSCP) and automated DNA sequencing, we analysed the mutations in the SRY gene in three 46,XY sex reversal patients. Two patients demonstrated nucleotide substitution (A
G) within the open reading frame just outside and upstream of the conserved DNA-binding motif called the high-mobility group (HMG) box, replacing glutamine at codon 57 with arginine. Altered SSCP patterns were also observed in these patients. Histological examination of gonads in patient 1 revealed the formation of gonadoblastoma. Patient 3 demonstrated AT substitution which replaces serine at codon 143 with cysteine, just outside but downstream of the HMG box. Results suggest the involvement of SRY gene in sex reversal which further supports the relationship between SRY alterations, gonadal dysgenesis and/or primary infertility. Key words: gonadoblastoma/SRY gene/46,XY sex reversal
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Introduction |
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Sex determination is governed and regulated by a series of genetic switches that influence cellular differentiation during critical periods of gonadal development. Interestingly, the primordial fetal gonads are bipotential and gonadal development provides an excellent opportunity to identify genes involved in the differential organogenesis. During mammalian embryogenesis, the presence of the SRY gene determines whether the gonads develop as testes, which in turn determines whether the embryo will develop as a male. In the absence of the SRY gene, the fetal gonads develop as ovaries (Harley et al., 1992
). XY gonadal dysgenesis is the result of an embryogenic testicular regression event, and can occur in a pure or partial form. Pure gonadal dysgenesis is defined as 46,XY individuals with no testes but who have fully developed female-type external genitalia and normal Müllerian structures but only streak gonads. In contrast, patients with partial gonadal dysgenesis are characterized by partial testicular differentiation with genital ambiguity. Gonadal histology illustrates hypoplastic testicular tubules intermixed with ovarian stroma (Marcantonio et al., 1994). These individuals may have unilateral or bilateral dysgenetic gonads and/or streak gonads.
Several genetic loci may play important roles in testis-determining pathways. Male-to-female sex reversal in patients with 46,XY karyotype results from the failure of testis development, which may be due to mutations in the SRY gene (Sinclair et al., 1990). This gene is located on the short arm of the Y chromosome close to the pseudo-autosomal boundary. It consists of a single exon with a conserved central motif, termed high-mobility group (HMG) box, and has DNA-binding as well as DNA-bending activities, suggesting that it functions as a transcriptional regulator. This gene has been shown to be essential for initiating testis development and the differentiation of the indifferent and bi-potential gonads into the testicular pathway (Sinclair et al., 1990; Marx, 1995). In the presence of SRY, the supporting cells of the undifferentiated gonad become testicular Sertoli cells, and without SRY the supporting cells become ovarian follicular cells (Capel, 2000). This protein has been shown to possess sequence-specific DNA-binding activity and it is assumed to regulate other genes involved in the male determination pathways (Harley et al., 1994). Normal SRY changes the architecture of DNA, thus allowing access of other factors needed for its expression (Behlke et al., 1993). SRY gene product stimulates a cascade of regulatory events, allowing Leydig cell differentiation from steroid secretory cells, the arrest of mitosis in germ cells and proliferation and organization of connective tissue into a testicular pattern (Castineyra et al., 2000). The HMG box is essential for SRY to bind and bend DNA, as well as for transporting the protein into the nucleus (Sinclair, 2001).
Different types of mutations in SRY gene have been found to account for 
15% of these cases with gonadal dysgenesis (Cameron and Sinclair, 1997;Margarit et al., 1998; Assumpcao et al., 2002). However, the majority of these patients may have mutations in other genes involved in the sex differentiation pathway or in the regulatory elements of SRY gene. To date, 51 mutations have been identified within the SRY gene open reading frame (Table I), and most of these are located in the HMG box, highlighting the crucial but critical role of this domain (Assumpcao et al., 2002; Fernandez et al., 2002; IMG; http://archive.uwcm.ac.uk/uwcm/mg/hgmd0.html; Zhou et al., 2003). Only 10 mutations lie outside and upstream of the HMG box (eight of which are located in the 5' region) and the remaining two lie downstream, 3' of the HMG box (IMG, http://archive.uwcm.ac.uk/uwcm/mg/hgmd0.html; Baldazzi et al., 2003). The analysis of SRY status in relation to female infertility has been done in most developed countries, yet to the best of our knowledge so far there are no reports (except one individual reported from India where the mutation lies within the HMG box: McElreavey et al., 1992) of SRY gene mutations outside of the HMG box that have been documented in correlation with cytogenetic and biochemical anomalies in infertile female patients (46,XY) with gonadal dysgenesis from developing countries, particularly India where reproductive health problems are still considered as a social stigma.
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Here we describe two novel point mutations in the SRY gene in three patients with 46,XY gonadal dysgenesis. An attempt has also been made to investigate the relationship between SRY mutations and gonadoblastoma formation in these patients. One mutation is found just outside, 5' upstream of the HMG box and the other outside, 3' downstream of the HMG box; both of these mutations are associated with variable phenotypes.
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Informed consent was obtained from all patients and control individuals who participated in the present study. This study was approved by the Ethics Committees both of the hospital and university.
Subjects
Patient 1, a 28 year old woman born to healthy unrelated parents, presented with primary amenorrhoea, but was otherwise healthy and had no history of illness. The patient had no dysmorphic features. The external genitalia and secondary sexual characteristics of this patient were like those of normal females. Other features included the presence of Müllerian structure, absence of Wolffian structures and formation of tubules. Pubic and sparse axillary hairs were also present. Pelvic ultrasound revealed streak gonads and presence of Müllerian ducts. Endocrine function studies showed elevated LH (28.4 mIU/ml) and FSH (69.2 mIU/ml). One atypical feature of the proband is the presence of secondary sexual characteristics including normal breast development. Histological examinations of the gonads also revealed proliferation of atypical germ cells admixed with granulomatous chronic inflammation consistent with gonadoblastoma formation.
Patients 2 and 3 were 22 and 20 year old females respectively born to healthy unrelated patients and were referred to us because of primary amenorrhoea. Both these patients had fully developed feminized phenotypes without any sexual ambiguity. Other features included presence of Müllerian structures, absence of Wolffian structures and formation of tubules with sparse axillary hairs. Pubic hair showed characteristic male-like distribution with clitoromegaly without any labial fusion. Pelvic ultrasound revealed the presence of streak gonads and presence of Müllerian ducts. The external genitalia and secondary sexual characteristics were like those of normal females. Endocrine function studies showed elevated LH (22.6 and 24.2 mIU/ml) and FSH (54.0 and 49.7 mIU/ml) respectively. Both patients had not developed any gonadoblastoma at the time of examination.
Three heparinized blood samples were collected from patients at the Department of Obstetrics and Gynaecology, Maulana Azad Medical College and Lok Nayak Hospital, New Delhi-110025 India and transported to the laboratory on ice. All patients and controls who participated in the present study were non-smokers and non-alcoholics.
Cytogenetic analysis
Chromosomal analyses were performed by conventional techniques on phytohaemagglutinin-stimulated peripheral blood culture from the infertile female patients (Husain and Bamezai, 1988). Conventional G-banding techniques were used for chromosome identification.
Hormonal analysis
The hormonal evaluation was conducted by the radioimmunoassay method using kits supplied by BARC, India (for LH) and Hormone Diagnostics, India (FSH).
SRY analysis
Genomic DNA from the blood samples was extracted by digestion with Proteinase K (Boehringer) followed by routine phenol chloroform isolation and precipitation with ethanol or isopropanol and chilled 3 M sodium acetate (pH 5.2). Vacuum-dried DNA samples were dissolved in TE (Tris–EDTA) buffer and DNA concentration was determined by gel electrophoresis. Two sets of oligonucleotide primers (F1 5'-CATGAACGCATTCATCGTGTGGTC-3'; R1 5'-CTGCGGGAAGCAACTGCAATTCTT-3', and F2 5'-CAGTGTGAAACGGGAGAAAACAGT-3'; R2 5'-GTTGTCCAGTTGCACTTCGCTGCA-3') were used in the PCR reactions to amplify fragments of 254 and 351 bp respectively from the open reading frame of the SRY gene. Exon 5 of the p53 gene was amplified as an internal control using oligonucleotide primers F5'-TACTCCCCTGCCCTCAACAA-3' and R5'-CATCGCTATCTGAGCAGCGC-3' yielding a PCR product of 184 bp. PCR amplification was performed in 25 ml reaction volume containing 10 mmol/l Tris–HCl (pH 8.4), 50 mmol/l KCl, 1.5 mmol/l MgCl2, 200 µmol/l each of dNTP (dATP, dCTP, dGTP, dTTP), 5 pmol of oligonucleotide primers, 100–500 ng of DNA and 0.5 IU Taq DNA polymerase (Perkin–Elmer Cetus, USA). PCR thermal cycling conditions were; a 4 min denaturation period at 95°C and 35 cycles of the following: 95°C for 30 s, 55°C for 30 s and 72°C for 30 s, and a final extension of 7 min at 72°C. Every PCR included negative (normal XX female) and positive (normal XY male) controls. PCR products (7.0 µl) were visualized on 2% agarose gel with ethidium bromide.
Single-strand conformational polymorphism (SSCP)
PCR products were labelled with [
-P32]dCTP by performing an additional 15 cycles of PCR and loaded on 6% non-denaturing polyacrylamide gel containing 5% glycerol. The electrophoresis was carried out overnight at 200 V at 17±1°C. The dried gel was exposed to X-ray film for 48 h at–70°C (Orita et al., 1989).
Automated DNA sequencing
PCR products showing altered band mobility and/or shift in SSCP patterns were sequenced using an ABI prism 310 automated sequencer. Before sequencing, PCR products were purified using ammonium acetate–ethanol precipitation method. The cycle sequencing of the purified PCR products was performed using BIG Dye terminator sequencing ready reaction mix with AmpliTaq DNA polymerase FS, on GeneAmp PCR 9700. PCR conditions were set as: 96°C x 10 s, 56°C x 5 s and 60°C x 4 min for 25 cycles. After cycle sequencing, extension products were purified to remove any unincorporated dye-labelled terminators using ethanol–sodium acetate precipitation method. Template suppressor reagent was added and samples were heat-denatured, chilled on ice and loaded on the 310 sequencer. The sequences were analysed using sequencing analysis software 3.4.1 on a Mac OS 9.1.
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Chromosome analysis from peripheral blood lymphocyte cultures showed a 46,XY karyotype in patients with primary infertility. Alterations of the investigated biochemical parameters were sufficient to exclude the diagnosis of androgen insensitivity. Based on these findings, we set up PCR to amplify the SRY gene. PCR products were also scanned for mutations using single strand conformational polymorphism (SSCP) analysis. All three samples showed aberrant migration in the SSCP assay (Figure 1
). By direct sequencing of PCR products, we have identified a point mutation in the SRY gene in patients 1 and 2. This mutation is an AG transversion mutation that results in the replacement of glutamine with an arginine residue at amino acid 57 in the open reading frame, just outside and upstream of conserved DNA-binding motif called HMG box (Figures 2A, B and 3). Gonadal examination revealed the presence of gonadoblastoma formation in patient 1. However, the third patient demonstrated AT transversion mutation which leads to the replacement of the serine residue at codon 143 with a cysteine residue, just outside but downstream of the HMG box sequence (Figures 2C, D and 3). Neither of the other mutations nor nucleotide mosaicisms were found in the amplified products of the SRY gene. No nucleotide substitution mutations were found in our preliminary SRY sequencing from 25 normal males excluding the possibility of a polymorphism. It cannot be ascertained whether these mutations are de novo as paternal DNA was not available for analysis and therefore a parental germ cell mosaicism cannot be excluded.
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Discussion |
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All three patients presented with a 46,XY karyotype and had no evidence of mosaicism. They had elevated FSH and LH levels, well-formed Müllerian structures, no Wolffian structures, streak gonads and fully formed feminized female genital structures. Patient 1 also had gonadoblastoma formation. There is evidence that the SRY gene is essential for sex determination (Sinclair et al., 1990
). The assignment of SRY as the testis-determining factor (TDF) is supported by many studies of human intersex abnormalities (Harley et al., 1992; McElreavey et al., 1992; Affara et al., 1993; Zeng et al., 1993; Bilbao et al., 1996; Brown et al., 1998). All these studies indicate that mutations in the SRY gene are associated with gonadal dysgenesis. The SRY protein belongs to the SOX family of transcription factors, which are further characterized by a HMG domain with DNA-binding and -bending properties, the ability to mediate protein–protein interactions, and containing signals for nuclear import (Südbeck and Scherer, 1997; Wilson and Koopman, 2002). Here, we describe three females with gonadal dysgenesis and mutations in the SRY gene at codon Q57R in patients 1 and 2 and S143C in patient 3. Both these mutations lie just outside the highly conserved HMG box. The polar neutral amino acid, glutamine, is replaced with a polar charged arginine (with pKa of 12.5) in patients 1 and 2. It is possible that with this mutation in place, mutated SRY protein may not be able to enter the nucleus to elicit the male gene expression or it may have disrupted the nuclear localization signal necessary to perform male gene expression. This change may form an electrostatic and hydrophobic interaction with phosphate and sugars respectively of DNA and could play an important role in altering the specific orientation and binding to DNA bases in the major groove. This may have totally or at least partially inhibited the interactions of SRY with DNA (Werner et al., 1995). Patient 1 has also got normal breast development which is an atypical feature of the phenotype. The older patient (no. 1) developed gonadal tumours where as the younger patient (no. 2) did not, which is further supported by previous studies (Manuel et al., 1976; Schmitt-Ney et al., 1993; Tajima et al., 1994; Uehara et al., 1999, 2002). It is widely recognized that dysgenetic gonads possibly due to the SRY mutations frequently develop gonadoblastoma. However, the molecular cause of gonadoblastoma formation remains elusive. The GBY (gonadoblastoma locus, Y chromosome) locus on Yq region is thought to contain a proto-oncogene involved in the origin of these tumours (Page, 1987). This is further supported in that mutations in oncogenes, tumour suppressor genes and DNA repair genes accumulate with age and then cause tumour development in the streak gonads (Knudson, 1971). Although many patients with mutations in the SRY gene fail to develop secondary sexual characteristics at puberty, a small subset, similar to patient 1, do develop these to varying degrees (Scully, 1970; Warner et al., 1985). Polar neutral amino acid serine is found replaced with a neutral and non-polar cysteine (with pKa 8.4) at codon 143 in patient 3. This change may result in an altered protein which may have lost some of its stabilizing potential.
The majority of the mutations detected so far in the SRY gene lie within the conserved motif, i.e. HMG box, causing alterations in DNA binding/bending activity, and possibly contributing to the origin of 46,XY females. To date, only 10 mutations that lie outside the HMG box have been detected and all have different effects on the patient phenotype. It is hypothesized that the regions outside the HMG box might be required to stabilize protein binding and to generate specificity by helping to discriminate between the protein–protein interactions (Wilson and Koopman, 2002). Proteins such as SRY possessing just one HMG box show sequence specificity for DNA binding by recognizing AT-rich sequences, thus inducing a bend in the DNA helix. DNA binding and bending capacities by SRY protein have been demonstrated to be essential in testis development (Harley et al., 1992). The strong bending of DNA together with the lack of a potential transregulation domain in human SRY has led to the suggestion that protein may modulate transcription by acting architecturally in the assembly of a nucleoprotein complex (Pontiggia et al., 1994). However, despite the critical role of SRY in the cascade of gene regulation leading to maleness, the direct targets of SRY remain to be positively identified.
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Acknowledgements |
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We thank the patients and controls who participated in this study, and the clinicians from Department of Obstetrics and Gynecology, Maulana Azad Medical College and Lok Nayak Hospital, New Delhi 110 002, India. This work was supported by a grant from Indian Council of Medical Research (No 3/1/2/18/2001-RHN), New Delhi 110 029, India.
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Submitted on February 23, 2004; resubmitted on March 30, 2004; accepted on April 26, 2004.
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