This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Canto, P. Articles by Méndez, J. P. Search for Related Content PubMed PubMed Citation Articles by Canto, P. Articles by Méndez, J. P. Pubmed/NCBI databases Gene GEO Profiles HomoloGene OMIM Protein UniGene Substance via MeSH Genetics Home Reference Medline Plus Health Information Turner Syndrome

A Mutation in the 5' Non-High Mobility Group Box Region of the SRY Gene in Patients with Turner Syndrome and Y Mosaicism¹

Research Unit in Developmental Biology, Hospital de Pediatría, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social (P.C., E.d.l.C., J.P.M.); Department of Biologic Systems, Ciencias Biologicas y de la Salud, Universidad Autónoma Metropolitana-Xochimilco (M.L.); Department of Genetics, Hospital General de México, Secretaria de Salud, Facultad de Medicina, Universidad Nacional Autonoma de Mexico (A.C., S.K.-A.); and Departments of Reproductive Biology (B.C., F.V., A.U.-A.) and Pathology (E.R.), Instituto Nacional de la Nutrición Salvador Zubirán, Mexico D.F., Mexico

Address all correspondence and requests for reprints to: Dr. Juan Pablo Méndez, Unidad de Investigación Médica en Biología del Desarrollo, Coordinación de Investigación Médica, Avenida Cuauhtémoc 330, Apartado Postal 73–032, Colonia Doctores, C.P. 06725, México D.F., Mexico. E-mail: jpmb{at}servidor.unam.mx

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
In Ullrich-Turner syndrome (UTS) patients, the presence of a Y-chromosome or Y-derived material has been documented in frequencies ranging from 4–61%. Mutations of SRY (testis-determining gene) constitute the cause of XY sex reversal in approximately 10–15% of females with pure gonadal dysgenesis. Most of these mutations have been described in the HMG (high mobility group) box of the gene, which is the region responsible for DNA binding and bending; however, various mutations outside the HMG box have been reported. We carried out molecular studies of the SRY gene in three patients with a UTS phenotype and bilateral streaks; two presented a 45,X/46,XY mosaic, and the third a Y marker chromosome.

In two patients a missense mutation, S18N, was identified in the 5'non-HMG box region in DNA from blood and both streaks; this mutation was not identified in 75 normal males. Sequencing of the DNA region of interest was normal in the father and older brother of patient 1, demonstrating that in this patient the mutation was de novo.

A previous report of a 46,XY patient with partial gonadal dysgenesis who presented the same mutation as our patients indicates the probable existence of a hot spot in this region of the SRY gene and strengthens the possibility that all gonadal dysgeneses constitute part of a spectrum of the same disorder. It also demonstrates that a single genetic abnormality can result in a wide range of phenotypic expression.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
VARIOUS STUDIES demonstrated that 40–60% of patients with Ullrich-Turner syndrome (UTS) were monosomic for the X-chromosome in peripheral blood lymphocytes, whereas the remaining patients had a structurally abnormal X- or Y-chromosome or were mosaics with a second cell line containing a normal or an abnormal sex chromosome (1). Using improved cytogenetic and molecular techniques, a higher frequency of mosaicism (66.7%), largely due to the presence of marker chromosomes (18.4%), was informed (2). Recent studies in which UTS patients with different karyotypes (45,X, mosaics and patients with a marker chromosome) were included have demonstrated the presence of a Y-chromosome or Y-derived material in frequencies ranging from 4–61% (3, 4, 5, 6, 7, 8). In UTS patients, the presence of a Y-chromosome is correlated with a 10–20% risk of developing gonadoblastoma or dysgerminoma (9).

Sex determination and differentiation are sequential processes regulated by an unknown number of gene loci located on sex and autosomal chromosomes that occur in the testis-determining pathway. However, there is wide evidence that the Y-located SRY gene directs testicular development (10). Organizing factors, gonadal steroids, peptide hormones, and tissue receptors are also involved in sex determination; interruption at any level will cause a sex differentiation disorder.

Point mutations, frame shifts, or deletions of SRY are among the known causes of XY sex reversal, and approximately 10–15% of XY females with pure gonadal dysgenesis (PGD) have mutations in the SRY gene (11). Most of these mutations are located in the highly conserved high mobility group region of the gene, which is responsible for DNA binding and bending (i.e. the HMG box). However, various mutations outside the HMG box have been reported; Brown et al. (12) described a 46,XY female with partial ovarian function who presented a Gln²Stop mutation, whereas several others have reported mutations in patients with complete or partial gonadal dysgenesis (13, 14, 15, 16).

As mosaic patients with Y-derived material present a variable phenotype, we decided to perform molecular studies of the SRY gene in three patients with a UTS phenotype and bilateral streaks, two with a 45,X/46,XY mosaic and the third with a Y marker chromosome. In two of them a missense mutation, S18N, was identified in the 5' non-HMG box region.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Informed consent was obtained from all subjects. Three unrelated phenotypic females with a diagnosis of UTS, in whom Y-derived material had been previously detected, were included. All three patients were of Mexican mestizo ethnic origin and from different geographic locations.

Patients

Case 1. The proposita presented at 14 yr of age with short stature, primary amenorrhea, and absence of pubertal development. She was the seventh of eight siblings (six females and two males). Clinical examination revealed a height of 126 cm, multiple Turner stigmata (i.e. micrognathia, low set ears, high arched palate, short and webbed neck, bilateral cubitus valgus, and multiple nevi), and sexual infantilism; no clitoromegaly was observed. Endocrinological studies showed the presence of hypergonadotropic hypogonadism (estradiol, <13.0 pg/mL; LH, 16.8 mIU/mL; FSH, 47.0 mIU/mL) as well as normal female concentrations of testosterone and androstenedione. Cytogenetic analysis in peripheral blood revealed a 45,X (498)/46,X,+mar (2). PCR detection of Y-specific sequences was positive for SRY, ZFY, and Y centromeric alphoid region and negative for PABY and Yq heterocromatic region. These data indicated that the marker chromosome is Y derived, with break points probably below PABY (Yp11.3) and above Yqh (Yq12) (6). By laparotomy, bilateral streak gonads were removed; a rudimentary uterus with a narrow lumen and atrophic Fallopian tubes were found. The karyotype in fibroblasts cultured from both gonads was 45,X (100%); although the possibility of mosaicism cannot be ruled out. The father and a 37-yr-old brother were also studied. Both individuals had a 46,XY karyotype in blood and were fertile, and clinical examination showed a normal male phenotype.

Case 2. She presented at 15 yr of age with short stature, primary amenorrhea, and absence of pubertal development. Physical examination showed a height of 131 cm, multiple Turner stigmata (i.e. low set ears, short neck, bilateral cubitus valgus, microthelia, and multiple nevi), and sexual infantilism; no clitoromegaly was observed. Hypergonadotropic hypogonadism (estradiol, <13.0 pg/mL; LH, 44.3 mIU/mL; FSH, 75.7 mIU/mL) with normal female concentrations of testosterone and androstenedione were detected. The karyotype in peripheral blood was 45,X (35%)/46,XY (65%). During laparotomy, bilateral streak gonads were removed, and a rudimentary uterus as well as two atrophic Fallopian tubes were found; no gonadal fibroblasts could be cultured in this patient due to contamination.

Case 3. The patient presented at 17 yr of age with short stature and primary amenorrhea. Somatic examination revealed a height of 138 cm, multiple Turner stigmata (i.e. epicanthal folds, deformed ears, high arched palate, shield-like chest, short neck, cubitus valgus, and multiple nevi). Scarce pubic hair (Tanner stage II) was observed; there was no clitoromegaly. Endocrinological studies demonstrated hypergonadotropic hypogonadism (estradiol, <13.0 pg/mL; LH, 26.0 mIU/mL; FSH, 38.8 mIU/mL) as well as normal female concentrations of testosterone and androstenedione. Blood karyotype was 45,X (82%)/46,XY (18%). Both streak gonads were removed, and an atrophic uterus with bilateral atrophic Fallopian tubes was observed. The karyotype in fibroblasts of the right streak was 45,X (98%)/46,XY (2%), whereas in the left streak the karyotype was 45,X (94%)/46,XY (6%).

Methods

Cytogenetic studies. Chromosome analysis was performed in 500 metaphases with GTG and CBG banding from peripheral blood leukocytes and in 100 metaphases from gonadal tissue.

Fluorescence in situ hybridization (FISH). FISH analysis was performed in preparations obtained from peripheral blood lymphocytes of patient 1 with probe Y97, which identifies a Y-centromeric alphoid region labeled by random primer with fluorescein-12-deoxy-UTP and with fluorescein-12-deoxy-UTP-labeled probe pDMXI (Roche Molecular Biochemicals, Mannheim, Germany), which detects alphoid sequences. The slides were dehydrated in a series of increasing ethanol concentrations (70%, 85%, and 100%) and denatured with the DNA probe in hybridization solution (65% formamide, 10% dextran sulfate, and 2 x SSC) for 5 min at 72 C in a prewarmed oven. After overnight hybridization at 37 C, in a moist chamber, the slides were washed twice for 5 min each time in 2 x SSC at room temperature and counterstained with propidium iodide in antifade solution. The signals were observed by fluorescence microscopy with a triple band filter for each probe; 500 nuclei were analyzed.

DNA analysis Genomic DNA was isolated from blood leukocytes of all three patients as well as from normal male controls using standard techniques (17). DNA was also isolated from paraffin-embedded gonadal tissue from the patients and controls as follows. Tissue slices (30 µm thick) were deparaffined twice in 1 mL xylene for 10 min, followed by two 100% ethanol rinses. Tissue pellets were dried in an 80 C heat block. Afterward, the tissue was treated with 150 µg/ml proteinase K in a 100 mmol/L Tris-HCl (pH 7.5), 10 mmol/L ethylenediamine tetraacetate, 100 mmol/L NaCl, and 10% SDS buffer at 48 C for 18 h. Proteinase K was heat inactivated by a 10-min incubation at 97 C. DNA was treated once with phenol-chloroform-isoamylethanol (25:24:1) and once with chloroform-isoamylethanol (24:1); afterward it was precipitated with 1 vol 2-propanol and washed with 70% ethanol. The pellet was dissolved in 20 µl ddH₂O.

PCR analysis. Genomic DNA from blood and gonads was used. PCR for SRY was performed as previously described (18), using the following oligonucleotides: 1) XES2 (5'-CTGTAGCGGTCCCGTTGCTGCGGTG-3') and XES7 (5'-CCCGAATTCGACAATGCAATCATATGCTTCTGC-3') at 94 C for 5 min, followed by 35 cycles of 94 C for 1 min, 68 C for 1 min, and 72 C for 2 min; this was terminated by 72 C for 10 min; and 2) XES10 (5'-GGTGTTGAGGGCGGAGAAATGC-3') and XES11 (5'-GTAGCCAATGTTACCCGATTGTC-3'), same as for XES2 and XES7.

After amplification, PCR products were electrophoresed in a 1.5% agarose gel stained with ethidium bromide and directly visualized by UV fluorescence. For all agarose gels, a 100-bp ladder (Life Technologies, Inc., Gaithersburg, MD) was used as size standard.

DNA sequencing. Mutant and control PCR products were purified by GeneClean (BIO-101, Vista, CA). Direct sequencing of PCR products was performed in both directions using the AmpliCycle Sequencing Kit (Perkin-Elmer Corp.-Roche, Branchburg, NJ), following the protocol supplied by the manufacturer. Sequencing reactions were run on a 6.0% polyacrylamide-7.5 mol/L urea gel. After electrophoresis, gels were dried and exposed to Kodak BioMax MR films (Eastman Kodak Co., Rochester, NY) for 12–14 h.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
A point mutation was detected in DNA from blood and both streaks of cases 1 and 3 at position 2128 of the SRY gene upstream the 5'-border of the HMG box. This mutation changed a guanine to an adenine, thereby causing an amino acid change from serine to asparagine at codon 18. We also analyzed the DNA from the father and older brother of patient 1. Direct sequencing of the DNA region of interest was normal in both individuals (Fig. 1). Male relatives of patient 3 did not want to participate in the study. We failed to identify this SRY mutation in 75 unrelated normal men. Patient 2 had a normal SRY sequence in blood.

View larger version (66K): [in this window] [in a new window]   Figure 1. Partial sequence of the SRY gene of patients 1, 2, and 3; from the father (F) and older brother (B) of patient 1; and from a normal male control (C). Observe the G to A substitution that changes the sense of codon 18 from serine to asparagine in patients 1 and 3.

Although only one representative example is shown, both strands were sequenced and compared. The mutation was confirmed in two independent PCR amplifications and sequencings from blood, left and right streaks.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Previous reports in UTS patients with different karyotypes (45,X, mosaics or patients with a marker chromosome) demonstrated the presence of a Y-chromosome or Y-derived material in frequencies ranging from 4–61% (3, 4, 5, 6, 7, 8). Sex determination in humans depends upon the action of the SRY gene, located on the short arm of the Y-chromosome. Mutations in this gene can cause failure of testicular development that may result in complete or partial male to female sex reversal (11). It has been proposed that although most UTS patients have a predominance of 45,X cells, smaller clones of cells with 46,XX, 46,XY, or abnormal sex chromosome complements are always present (5). Held et al. (2) even suggested that mosaicism in UTS is a prerequisite for survival in early pregnancy. Our finding in patient 1 that only 2 of 500 cells presented Y-derived material demonstrates that in some patients who apparently are 45,X, a second cell line could be present in a very small proportion. In addition, it has been reported that chromosomal mosaicism can be unevenly distributed between different tissues in the same individual (2).

In the present study we found a missense mutation in the 5' non-HMG box region of the SRY gene in two patients with UTS and Y mosaicism. Mutations of SRY are among the known causes of 46,XY PGD (11). It has been generally accepted that mutations in the HMG box disrupt the gene’s function. Likewise, mutations outside the HMG box have been reported in several patients with PGD, and one has been detected in a 46,XY female with partial ovarian function (12, 13, 14, 15, 16).

To assess whether the mutation of case 1 was de novo, we analyzed the DNA from her father and older brother. In both cases the SRY gene was normal, demonstrating that the mutation was de novo. Although most of the mutations described in the SRY gene are de novo, some cases of fertile fathers and their XY daughters sharing the same altered SRY sequence have been reported (19, 20, 21, 22, 23). The presence of a mutation in a normal father does not exclude the possibility that such mutation is the cause of sex reversal, which is explained by the presence of gonadal mosaicism in the father and variable penetrance of the mutation, depending on the genetic background affecting the level of SRY expression (22, 23, 24, 25).

The S18N mutation was not identified in 75 normal males studied by us or in 50 other controls analyzed at this particular region in a previous study (16), making the possibility of polymorphism very unlikely.

Gonadal dysgenesis comprises a variety of clinical conditions characterized by an abnormal development of the fetal gonad. It includes 45,X UTS and its variants, mixed gonadal dysgenesis, as well as 46,XX and 46,XY PGD. The latter encompasses a complete and a partial form. Except in the partial form of 46,XY PGD where bilateral dysgenetic testes are formed and in mixed gonadal dysgenesis where generally a streak gonad and a testis besides an ambiguous phenotype are observed, in all other entities bilateral streak gonads and a female phenotype are always present (26). In most patients with 45,X UTS, bilateral streak gonads are formed; however, approximately 5% of these girls have some ovarian function (27, 28). Interestingly, in some patients with the complete form of 46,XY PGD, ovarian differentiation has been observed (12, 26). Patients with a 45,X/46,XY karyotype present a great clinical variability that ranges from a male phenotype with dysgenetic testes to females with bilateral streaks and UTS phenotype (29); however, 90% of the fetuses diagnosed by amniocentesis and confirmed postnatally as 45,X/46,XY mosaics exhibited normal male genitalia (30). Interestingly, the same mutation found in two of our patients was reported previously by Domenice et al. (16), in a 46,XY patient with partial gonadal dysgenesis who presented an abnormal testis, which indicates the probable existence of a hot spot in this region of the SRY gene. These data strengthen the possibility that all of these entities, including UTS, constitute part of a spectrum of the same disorder. Recently, Takayi et al. (31) reported a 45,X/47,XYY phenotypical female with a frame-shift mutation at position 422 of the SRY gene, concluding that this mutation explained the presence of bilateral streaks and female phenotype observed in the affected individual.

It has been proposed that early events after Sry expression in mice result in the topographical organization of diverse cell types making up the developing testis. The Sry protein must regulate multiple pathways of gene expression, including those that control morphogenic mechanisms (32). As recently proposed by Cameron and Sinclair (11), a given mutation in SRY may produce sufficient SRY activity to reach the threshold required for testis formation. However, the same mutation on a different genetic background may reduce SRY activity, preventing testis development.

We consider that in both patients the predominance of the 45,X cell line besides the existing mutation prevented the development of testicular tissue. The magnitude in which the 45,X cell line or the SRY mutation affected the existing phenotype cannot be ascertained.

	Footnotes

 
¹ This work was supported by the Consejo Nacional de Ciencia y Tecnología, Mexico City, Mexico (Grants 3008P-M9608 and 212226–5-G0016M), and the Coordinación de Investigación Médica, Instituto Mexicano del Seguro Social, Mexico (Grant FP0038/181).

² Postdoctoral research fellow supported by a CONACYT fellowship award.

³ Present address: Research Unit in Reproductive Medicine, Hospital de Ginecobstetricia Luis Castelazo Ayala, Instituto Mexicano del Seguro Social, Mexico D.F., Mexico.

Received September 24, 1999.

Revised February 1, 2000.

Accepted February 2, 2000.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

1. Hall J, Gilchrist D. 1990 Turner syndrome and its variants. Pediatr Clin North Am. 37:1421–1440.[Medline]
2. Held KR, Keber S, Kaminsky E, et al. 1992 Mosaicism in 45,X Turner syndrome: does survival in early pregnancy depends on the presence of two sex chromosomes? Hum Genet. 88:288–294.[Medline]
3. Binder G, Koch A, Wajs E, Ranke M. 1995 Nested polymerase chain reaction study of 53 cases with Turner’s syndrome: is cytogenetically undetected Y mosaicism common? J Clin Endocrinol Metab. 80:3532–3536.[Abstract]
4. Coto E, Toral J, Menéndez M, et al. 1995 PCR-Based study of the presence of Y-chromosome sequences in patients with Ullrich-Turner syndrome. Am J Med Genet. 57:393–396.[CrossRef][Medline]
5. Fernández R, Méndez J, Pásaro E. 1996 Turner syndrome: a study of chromosomal mosaicism. Hum Genet. 98:29–35.[CrossRef][Medline]
6. López M, Canto P, Aguinaga M, et al. 1998 Frequency of Y chromosomal material in Mexican patients with Ullrich-Turner syndrome. Am J Med Genet. 76:120–124.[CrossRef][Medline]
7. Patsalis PC, Sismani C, Hadjimarcou MI, et al. 1998 Detection and incidence of cryptic Y chromosome sequences in Turner syndrome patients. Clin Genet. 53:249–257.[Medline]
8. Quilter CR, Taylor K, Conway GS, Nathwani N, Delhanty JD. 1998 Cytogenetic and molecular investigations of Y chromosome sequences and their role in Turner syndrome. Ann Hum Genet. 62:99–106.[CrossRef][Medline]
9. Verp MS, Simpson JL. 1987 Abnormal sexual differentiation and neoplasia. Cancer Genet Cytogenet. 25:191–218.[CrossRef][Medline]
10. Goodfellow PN, Lovell-Badge R. 1993 SRY and sex determination in mammals. Annu Rev Genet. 27:71–92.[CrossRef][Medline]
11. Cameron FJ, Sinclair AH. 1997 Mutations in SRY and SOX9: testis-determining genes. Hum Mut. 9:388–395.[CrossRef][Medline]
12. Brown S, Yu CC, Lanzano P, et al. 1998 A de novo mutation (Gln2Stop) at the 5'end of the SRY gene leads to sex reversal with partial ovarian function. Am J Hum Genet. 62:189–192.[CrossRef][Medline]
13. McElreavy K, Vilain E, Abbas N, et al. 1992 XY sex reversal associated with a deletion 5' to the SRY HMG box in the testis-determining region. Proc Natl Acad Sci USA. 89:11016–11020.[Abstract/Free Full Text]
14. Tajima T, Nakae J, Shinohara N, Fujieda K. 1994 A novel mutation localized in the 3' non-HMG box region of the SRY gene in 46,XY gonadal dysgenesis. Hum Mol Genet. 3:1187–1189.[Free Full Text]
15. Veitia R, Ion A, Barbaux S, et al. 1997 Mutations and sequence variants in the testis-determining region of the Y chromosome in individuals with a 46,XY female phenotype. Hum Genet. 99:648–652.[CrossRef][Medline]
16. Domenice S, Nishi MY, Correia Billerbeck AE, et al. 1998 A novel missense mutation (S18N) in the 5' non-HMG box region of the SRY gene in a patient with partial gonadal dysgenesis and his normal male relatives. Hum Genet. 102:213–215.[CrossRef][Medline]
17. Sambrook J, Fritsch EF, Maniatis T. 1989 Isolation of high-molecular weight DNA from mammalian cells. In: Nolan C, ed. Molecular cloning: a laboratory manual. Cold Spring Harbor: Cold Spring Harbor Laboratory; 9.16–9.23.
18. Affara N, Chalmers IJ, Ferguson-Smith MA. 1993 Analysis of the SRY gene in 22 sex-reversed XY females identifies for new point mutations in the conserved DNA binding domain. Hum Mol Genet. 2:785–789.[Abstract/Free Full Text]
19. Berta P, Hawkins JR, Sinclair AH, Taylor A, Griffiths BL, Goodfellow PN. 1990 Genetic evidence equating SRY and the testis-determining factor. Nature. 348:448–450.[CrossRef][Medline]
20. Hawkins JR, Taylor A, Goodfellow PN, Migeon CJ, Smith KD, Berkovitz GD. 1992 Evidence for increased prevalence of SRY mutations in XY females with complete rather than partial gonadal dysgenesis. Am J Hum Genet. 51:979–984.[Medline]
21. Jäger RJ, Harley VR, Pfeiffer RA, Goodfellow PN, Scherer G. 1992 A familial mutation in the testis-determining gene SRY shared by both sexes. Hum Genet. 90:350–355.[Medline]
22. Schmitt-Ney M, Thiele H, Kaltwaber P, Bardoni B, Cisternino M, Scherer G. 1995 Two novel SRY missense mutations reducing DNA binding identified in XY females and their mosaic fathers. Am J Hum Genet. 56:862–869.[Medline]
23. Bilbao JR, Loridan L, Castaño L. 1996 A novel postzygotic non-sense mutation in SRY in familial XY gonadal dysgenesis. Hum Genet. 97:537–539.[Medline]
24. Hines RS, Tho SPT, Zhang YY, et al. 1997 Paternal somatic and germ-line mosaicism for a sex-determining region on Y (SRY) missense mutation leading to recurrent 46,XY sex reversal. Fertil Steril. 67:675–679.[CrossRef][Medline]
25. Capel B. 1998 Sex in the 90’s: SRY and the switch to the male pathway. Annu Rev Physiol. 60:497–523.[CrossRef][Medline]
26. Berkovitz GD, Fechner PY, Zacur HW, et al. 1991 Clinical and pathologic spectrum of 46,XY gonadal dysgenesis: its relevance to the understanding of sex differentiation. Medicine. 70:375–383.[Medline]
27. Palmer CG, Reichmann A. 1979 Chromosomal and clinical findings in 110 females with Turner syndrome. Hum Genet. 35:35–49.
28. Hall JG, Sybert VP, Williamson RA. 1982 Turner’s syndrome. West J Med. 137:32–34.[Medline]
29. Méndez JP, Ulloa-Aguirre A, Kofman-Alfaro S, et al. 1993 Mixed gonadal dysgenesis: clinical, cytogenetic, endocrinological, and histopathological findings in 16 patients. Am J Med Genet. 46:263–267.[CrossRef][Medline]
30. Chang HJ, Clark RD, Bachman H. 1990 The phenotype of 45,X/46,XY mosaicism: an analysis of 92 prenatally diagnosed cases. Am J Med Genet. 43:156–168.
31. Takagi A, Imai A, Tamaya T. 1999 A novel sex-determining region on Y (SRY) nonsense mutation identified in a 45,X/47,XYY female. Fertil Steril. 72:167–169.[CrossRef][Medline]
32. Martineau J, Nordqvist K, Tilmann C, Lovell-Badge R, Capel B. 1997 Male-specific cell migration into the developing gonad. Curr Biol. 7:958–968.[CrossRef][Medline]

This article has been cited by other articles:

				Y. Wang, S. Ristevski, and V. R. Harley SOX13 Exhibits a Distinct Spatial and Temporal Expression Pattern During Chondrogenesis, Neurogenesis, and Limb Development J. Histochem. Cytochem., December 1, 2006; 54(12): 1327 - 1333. [Abstract] [Full Text] [PDF]

				M. Shahid, V. S. Dhillon, M. Aslam, and S. A. Husain Three New Novel Point Mutations Localized within and Downstream of High-Mobility Group-box Region in SRY Gene in Three Indian Females with Turner Syndrome J. Clin. Endocrinol. Metab., April 1, 2005; 90(4): 2429 - 2435. [Abstract] [Full Text] [PDF]

				B. K. Jordan, M. Jain, S. Natarajan, S. D. Frasier, and E. Vilain Familial Mutation in the Testis-Determining Gene SRY Shared by an XY Female and Her Normal Father J. Clin. Endocrinol. Metab., July 1, 2002; 87(7): 3428 - 3432. [Abstract] [Full Text] [PDF]

				T. Yorifuji, J. Muroi, M. Mamada, A. Uematsu, M. Kawai, T. Momoi, M. Kaji, C. Yamanaka, and T. Nakahata Analysis of the SRY gene in Turner syndrome patients with Y chromosomal material J. Med. Genet., November 1, 2001; 38 (11): e41 - e41. [Full Text] [PDF]

This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Canto, P. Articles by Méndez, J. P. Search for Related Content PubMed PubMed Citation Articles by Canto, P. Articles by Méndez, J. P. Pubmed/NCBI databases Gene GEO Profiles HomoloGene OMIM Protein UniGene Substance via MeSH Genetics Home Reference Medline Plus Health Information Turner Syndrome