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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 10 4028-4036
Copyright © 2006 by The Endocrine Society

A Novel Human Sex-Determining Gene Linked to Xp11.21-11.23

Singh Rajender1, Kumarasamy Thangaraj1, Nalini J. Gupta, N. Leelavathy, Deepa Selvi Rani, Renjini G. Nambiar, Vadivelu Kalavathy, Sathiyavedu T. Santhiya, Sayee Rajangam, Puthiya M. Gopinath, Baidyanath Chakravarty and Lalji Singh

Centre for Cellular and Molecular Biology (S.R., K.T., D.S.R., L.S.), Hyderabad 500 007, India; Institute of Reproductive Medicine (N.J.G., B.C.), Salt Lake, Kolkata 700 091, India; Division of Human Genetics (N.L., S.R.), St. John’s Medical College, Bangalore 560 034, India; Department of Genetics, Postgraduate Institute of Basic Medical Sciences (R.G.N., V.K., S.T.S., P.M.G.), University of Madras, Chennai 600 113, India; and KMC Life Science Centre (P.M.G.), Manipal Academy of Higher Education, Manipal 576 104, India

Address all correspondence and requests for reprints to: Dr. K. Thangaraj and Dr. Lalji Singh, Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad 500 007, India. E-mail: thangs@ccmb.res.in and lalji{at}ccmb.res.in.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results and Discussion
 References
 
Context: The molecular basis for about 70–80% of 46,XY sex-reversed females remains unexplained, because they carry normal copies of the genes (SRY, SOX9, DAX1, DMRT, SF1, WT1) involved in sex determination pathway.

Objective: The objective of this study is to map the chromosomal locus responsible for an unexplained sex-reversed phenotype.

Design: The study implemented a genome-wide scan using families with multiple sex-reversed individuals.

Setting: The patients, along with the family members, were selected from different hospitals/reproductive centers.

Participants: Sex-reversed individuals and their siblings and parents participated in the study.

Main Outcome Measures: Identification of the chromosomal locus responsible for sex reversal in these families and sequence analysis of candidate genes were the main outcome measures.

Results: Parametric linkage analysis revealed a maximum two-point LOD score of 5.70 with marker DXS991 (Xp11.21) and 4.57 with marker DXS1039 (Xp11.23-Xp11.22), and a multipoint LOD score of 5.77 with marker DXS991 and 5.22 with marker DXS1039. The two markers (DXS991 and DXS1039) with highest LOD score span approximately 3.41 cM (75.79–79.2 cM) on the short arm of the X-chromosome.

Conclusion: Our findings provide evidence for a major susceptibility locus for sex reversal/gonadal dysgenesis on the short arm of the X-chromosome (Xp11.21-11.23). Furthermore, molecular exploration of the expression of candidate genes in the embryonic gonad/gonadal ridge will help in the identification of the underlying gene for sex reversal.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results and Discussion
 References
 
IN MAMMALS, THE SRY (sex-determining region on Y-chromosome) gene induces testis formation from the indifferent gonad (1). Another member of the SRY-HMG box family (SOX9) has also been shown to play a crucial role in testis differentiation (2). Recently, Qin and Bishop (3) have provided evidence that in mice Sox9 is sufficient for functional testis development in the absence of Sry. Campomelic dysplasia, caused by mutation(s) in SOX9 (SRY-related HMG-box9), is often associated with XY sex reversal (2), whereas mutations in the WT1 gene result in XY sex reversal associated with Denys-Drash syndrome (4) or Frasier syndrome (5). Duplication of Xp21, harboring the DAX1 gene (6), and mutations in the steroidogenic factor (SF1) (7) are known to cause XY sex reversal associated with kidney failure in the early stages of life. Relatively rarely, deletion of the DMRT genes on 9p has also resulted in XY sex reversal (8).

Despite the identification of the above genes, SRY was still the major sex-determining gene, and it was thought that the presence of SRY was mandatory for the male phenotype. However, the absence of SRY and apparently all other Y-chromosomal sequences in a substantial number of XX males and in most true hermaphrodites (9), and its presence in the majority of XY females who have no detectable SRY mutations (10), cannot be explained satisfactorily on the basis that the mere presence of SRY determines maleness. Evidence for an X-specific gene involved in sex determination was first postulated on the basis of a family with 46,XY gonadal dysgenesis (11). Affara (12) also suggested the presence of at least one additional key gene on the X-chromosome, downstream to SRY in the human sex-determining pathway. Furthermore, in certain reptiles (crocodilians and turtles), the incubation temperature of the egg determines the sex (13). These facts strongly suggest that certain gene(s) responsible for the differentiation of testes and ovary must be present in all the embryos. Thus determination, development, and differentiation of mammalian testes and ovaries from an embryonic bipotential gonad are controlled by a number of key genes interacting in an as yet poorly defined pathway (14).

Genes involved in sex determination have been identified mainly by deletion/duplication or translocation mapping in the cases of sex reversal/ambiguous sex. The fortuitous finding of chromosomal rearrangements in association with a sex-reversed phenotype has led to the isolation of the SRY and SOX9 genes (2, 3). Duplication of the distal Xp region resulted in the identification of DAX1 (6) and deletion studies resulted in the isolation of DMRT1/2/3 (15) and WT1 (16) from the short arms of chromosomes 9 and 11, respectively. The orphan nuclear receptor, SF1, was identified by targeted disruption of the Ftz-F1 gene in mice (17, 18).

Linkage studies to identify sex-determining genes are hampered by variation of the phenotypes in the affected families and the relative rarity of multigenerational pedigrees with several affected cases. Although many studies have reported familial cases of 46,XY gonadal dysgenesis (19, 20, 21), to our knowledge only two linkage studies for gonadal dysgenesis/sex reversal have been attempted thus far, of which one suggested linkage to chromosome 5 and the other also suggested involvement of an autosomal gene but could not establish strong linkage (22, 23). Therefore we have undertaken a genome-wide scan on nine familial cases of 46,XY sex reversal, which could not be explained by mutations in any of the known sex-determining genes, to search for additional chromosomal region(s) linked with sex reversal/gonadal dysgenesis.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results and Discussion
 References
 
Sex-reversal families

A total of 15 46,XY sex reversal families with gonadal dysgenesis were collected from different regions of India through our collaborating organizations. A proper phenotype (Table 1Go) was set for the selection of the familial cases. Five families with varying phenotype among siblings were excluded from the study to avoid locus heterogeneity. After molecular genetic analysis, nine families were finally selected for linkage analysis, which comprised a total of 58 individuals, including 17 patients and 35 informative individuals. Each family included in the linkage study had both parents with at least two informative individuals and no history of consanguinity (Fig. 1Go). All the participants donated blood samples with informed written consent. The study was approved by the institutional ethical committee.


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  		TABLE 1. Clinical features of all the sex-reversed patients

 

Figure 1
Figure 1
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  		FIG. 1. Pedigrees of the families studied.

 
Hormone assays

Serum levels of testosterone, 17-hydroxyprogesterone, FSH, and LH for the probands and the affected siblings were measured by RIAs.

Cytogenetic analysis

Peripheral blood lymphocyte cultures for all the family members were set up in duplicate in 5-ml culture vials using RPMI media supplemented with 10% fetal calf serum. Cells were grown in the presence of penicillin/streptomycin/gentamycin. Phytohemagglutinin was added to stimulate cell division. Dividing cells were arrested at metaphase stage with colchicin and fixed in methanol/acetic acid (3:1). Fixed cells were dropped onto glass slides and allowed to air-dry. Chromosomes were G-banded by treating the preparations with trypsin followed by staining with giemsa.

Histological studies

Histological studies were done for 11 of 17 patients because the others were below puberty. Gonadal tissue of the proband and other affected individuals was fixed using 10% buffered neutral formalin solution at room temperature for 7 d. Tissue was dehydrated with isopropanol, cleared with xyline at room temperature, and impregnated with paraffin wax at 58 C. Tissue embedded in paraffin wax was cut into 4-µm-thick sections using LeicaRM2135 microtome (Leica, Bensheim, Germany). The sections were taken directly on egg albumin-coated glass slides and kept at 60 C for 1 h. Slides were dewaxed with xyline and stained with hematoxylin followed by eosin. After staining, slides were mounted with dipthyline xyline and observed using Axioplan imaging system (Zeiss, Oberkochen, Germany), and images were captured at different magnifications.

PCR and sequencing of the known sex-determining genes

DNA was extracted from peripheral blood samples of all the participants using protocol described elsewhere (24). PCR primers for SRY and DAX1 were as used in earlier studies (25, 26), whereas primers for SOX9, SF1, and WT1, including the splice junctions (Supplemental Table S1, published as supplemental data on The Endocrine Society’s Journals Online web site at http://jcem.endojournals.org), were designed using GeneTool software and synthesized using 394 DNA/RNA oligosynthesizer (Applied Biosystems, Foster City. CA). Exonic regions of the above genes were amplified and sequenced using dideoxy chain terminator cycle sequencing protocol (BigDye) and 3700 DNA analyzer (Applied Biosystems) (27).

Sequencing of the candidate genes

The candidate genes were selected on the basis of their expression pattern and the putative role as transcription factors. We sequenced the coding regions of WD repeat domain 13 (WDR13), melanoma antigen family D, 1 (MAGED1), Kruppel-like factor 8 (KLF8), and zinc finger protein 157 (ZNF157) genes. The primers for sequencing the aforementioned genes were designed to include the splice junctions (Supplemental Table S1). Synthesis of primers and the sequencing methods used were as mentioned above.

Genotyping

In the first phase of genotyping, 437 Microsatellite markers (Linkage Mapping Set, MD10, V 2.5; Applied Biosystems), spanning the entire human genome, were amplified individually in 10 µl PCR. In the second phase of genotyping, 11 high-density markers (HDM) were amplified and genotyped. In the third phase of analysis, 26 micro-density markers (MDM) were amplified to check for recombination in the region of interest. For each linkage panel, amplicons were pooled in different ratios, depending upon the fluorescent label, and analyzed on ABI3730 DNA Analyzer (Applied Biosystems) using LIZ 500 as size-standard. The raw data were further analyzed using GeneMapper software. Same markers were amplified for control DNA (CEPH, 1347-02) and conversion table made for all the markers to avoid errors in sizing alleles, arising due to run-to-run differences.

Statistical analysis

In each phase of linkage mapping, two-point LOD scores were calculated using FASTLNIK package (28), assuming autosomal dominant model of inheritance for autosomal markers and X-linked recessive mode of inheritance for the X-linked markers. Multipoint linkage analysis was done for the markers in the critical region of the X-chromosome. The abnormality was assumed to have full penetrance and an allele frequency of 0.001. Simulation studies were done using MEGA2 (29) and SIMULATE (30) programs.


   Results and Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results and Discussion
References
 
On average, one in every 10,000 male individuals is sex reversed. However, the phenotype in the resulting cases can vary from nearly normal external male genitalia to entirely female genitalia, accompanied by various combinations of normal, mixed, or streak gonads. Over the last 10 yr, we have identified 15 familial cases of 46,XY male-to-female sex reversal presenting with gonadal dysgenesis from different parts of India, through our collaborating hospitals. To reduce problems arising from locus heterogeneity, a consistent phenotype (Table 1Go) was used for selection of the families for linkage analysis. Of the 15 families, 10 fulfilled these phenotypic criteria (Table 1Go). Therefore, these were candidates for linkage analysis directed at searching novel chromosomal region(s) linked to sex reversal.

The absence of additional phenotypic features associated with Campomelic dysplasia, Denys-Drash, and Frasier syndrome excluded the involvement of the SOX9, DAX1, WT1, and SF1 genes in all these families. Patient samples from each of the 10 families were subjected to sequencing of the known sex-determining genes (SRY, SOX9, DAX1, WT1, and SF1) to see whether the abnormality could be attributed to mutation in any of these genes. This analysis revealed that one family carried a partial deletion of the SRY gene, but detected no mutations in the remaining nine families. Each of the nine families included in the linkage study consisted of both parents with at least two informative individuals, and had no history of consanguinity (Fig. 1Go). Despite the apparent X-linked mode of inheritance of the sex-reversed phenotype in all the families, a genome-wide scan was performed to explore the possibilities of linkage to chromosomal region(s) other than the X-chromosome.

In the first phase of the analysis, a genome-wide scan was performed with 400 low-density short tandem repeat markers (average heterozygosity 0.79) spaced at an average resolution of 9.22 cM and spanning the whole human genome (Linkage Mapping Set MD10, V 2.5; Applied Biosystems). All the pedigrees were consistent with X-linked recessive mode of inheritance, although a sex-limited autosomal dominant mode could not be excluded. We performed parametric linkage analysis because of the higher power of parametric methods to detect linkage than nonparametric ones. For parametric analysis with the autosomal markers, autosomal dominant model was assumed. For all the X-specific markers, an X-linked recessive model of inheritance was assumed. The disease was assumed to have full penetrance with an allele frequency of 0.001. Two-point analysis was performed for all the markers using the FASTLINK package (28), but multipoint linkage analysis was carried out only for the markers in the critical region of the X-chromosome. Although many regions on different chromosomes yielded a LOD score of more than 1.0 (Table 2Go), a maximum two-point LOD score of 5.70 ({theta} consistent at 0.00 for all of the nine families) and multipoint LOD score of 5.77 ({theta} consistent at 0.01 for all of the nine families) was observed with the marker DXS991 on the X-chromosome (Tables 3Go and 4Go and Figs. 2Go and 3Go). All the families analyzed showed consistent linkage with marker DXS991 (Fig. 1Go). This narrowed the region of interest to approximately 30 cM on the short arm of the X-chromosome.


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  		TABLE 2. Autosomal markers with a maximum two-point LOD score of more than 1.0

 

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  		TABLE 3. Maximum two-point LOD scores for most critical markers on the X chromosome

 

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  		TABLE 4. Maximum multi-point LOD scores for most critical markers on X chromosome

 

Figure 2
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  		FIG. 2. Ideogram of the X-chromosome indicating the map positions of the low-density (LDM), HDM, and MDM short tandem repeat markers. The genetic distances (centimorgans) between the markers are also indicated. Markers with LOD scores of more than 2 are highlighted with a dark blue background. MDM with no recombination in any of the families are highlighted with a dark brown background.

 

Figure 3
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  		FIG. 3. Plot showing maximum two-point LOD score values across the genome. For each chromosome, the marker with maximum LOD score has been shown.

 
In the second phase of analysis, 11 HDM flanking DXS991 were selected for further mapping (average heterozygosity 0.77 and resolution 4.6 cM) (Applied Biosystems) (Fig. 2Go). Analysis with these markers resulted in a maximum two-point LOD score of 4.57 ({theta} consistent at 0.00 for all of the nine families) (Table 3Go) and multipoint LOD score of 5.22 ({theta} consistent at 0.00 for all of the nine families) with marker DXS1039, just adjacent to DXS991 (Table 4Go and Fig. 4Go). A marginally significant maximum two-point LOD score of 1.99 ({theta} consistent at 0.00 in all of the nine families) and multipoint LOD score of 4.51 ({theta} consistent at 0.10 in all of the nine families) was observed with DXS1216 also, a marker next to DXS1039. Linkage with DXS1039 was observed in seven families; the remaining two families were uninformative because of homozygosity in the mother (Fig 1Go). This further narrowed the region of interest to approximately 7.19 cM.


Figure 4
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  		FIG. 4. Multipoint LOD plot for the X-chromosome.

 
In the third phase of analysis, 26 micro-dense markers with an average resolution of less than 1 cM (deCODE map) were selected from this region to narrow further (Fig. 2Go). Genotyping with these markers revealed recombination between the trait and the DXS1216 marker in three families, which helped to reduce further the size of the region by 3.78 cM. As expected, none of the nine families linked to DXS991 and DXS1039 (phase 1 and 2) showed recombination between the disease phenotype and the MDMs that lay between the two most critical markers (DXS991 and DXS1039), suggesting strong linkage between these markers and the trait. This region spans approximately 3.41 cM (75.79–79.2 cM, deCODE map) on the short arm of X-chromosome (Fig. 2Go). A founder effect for the consistent linkage to the same chromosomal regions is unlikely because none of the affected individuals belonging to different families shared any common haplotype. Furthermore, they belonged to different linguistic affiliations and geographical regions (Supplemental Table S2). Absence of linkage to the known sex-determining regions (9q33, 11p13, Xp21, 17q24) further excluded the possibility of involvement of the genes residing in these loci (SF1, WT1, DAX1, SOX9).

To estimate the probability of getting a LOD score of 5.77 by chance, simulation studies with 1000 unlinked replicates were conducted using the MEGA2 (29) and SIMULATE (30) software packages. The LOD score in the simulation studies never exceeded 2.5 (threshold LOD score) at P = 0.05. The statistical analysis was repeated with different marker allele frequencies (including an increase of the minor allele and decrease of the major allele frequencies), to estimate their effect on our results. However, the results were robust to variation in marker allele frequencies.

Interestingly, no previous study has reported the involvement of Xp11.21-11.23 in sex reversal. Because the mutation(s) in the underlying gene in the present cases resulted in gonadal dysgenesis, this gene must have a role in testis differentiation/sex determination. The geographical distribution of the families used in this study does not indicate the common ancestry and hence founder effect. According to the X-chromosome gene annotation available in human genome database, at least 53 genes map to Xp11.21-11.23. Several of the genes involved in gonadal development described to date are transcription factors, and hence the ZNF family genes and some members of the SSX, MAGE, GAGE, and ZNF gene families, which are transcription factors, may be the likely candidates for sex determination. An earlier in silico study involving the search of the human genome for inverted repeat palindromes revealed many genes in the above region of the X-chromosome, of which some members of SSX, GAGE, and MAGE gene families were found to be expressed in testis (31). Our earlier study on screening of a human testis cDNA library with a Bkm (Banded Krait Minor satellite DNA) probe resulted in the isolation of a highly conserved WDR13 gene from Xp11.23. This gene is another potential candidate for sex determination, given high activity of its promoter in fetal and adult testes (32). Xp11.23 and the region distal to this are conserved in monotremes, marsupials, and placental mammals and were translocated from autosomes (33). Given that mammalian sex chromosomes evolved as specialized chromosome pair for sex determination, the evolutionary history also supports the presence of some sex-determining gene(s) in this region of the X-chromosome.

DNA sequence analysis of four candidate genes (WDR13, MAGED1, KLF8, ZNF157) in XY females did not reveal any mutation in any of these genes. Because the sex of the embryo is determined at the very early embryonic stages, the sex-determining genes must express during the early stages of gonad differentiation, the expression of which may reduce or cease all together in adult testes. The expression of a gene in adult testis doesn’t signify its expression in the indifferent gonad as well. The lack of the information about the expression of the genes in the candidate region in the indifferent gonad is the major complicating factor in the selection of the candidate genes more precisely and hence finding the underlying gene. Therefore, it is not sure whether the genes sequenced were really the top candidate genes for the sex-reversed phenotype (46,XY female). This may be one of the reasons why sequencing of four candidate genes did not reveal any mutation in the cases. To select the candidate genes more precisely, the information regarding the expression of these genes in the indifferent gonad is must. Availability of such information in databases would be immensely useful for selecting the right candidate gene(s).

Successful mapping of gonadal dysgenesis/sex reversal on the X-chromosome in the present study will fuel the search for further sex-determination genes and encourage such studies to explore the full sex-determination pathway. Mapping of the sex-reversed phenotype to the same locus in all the families studied reflects the importance of careful selection of the cases. This study is the first of its kind with multiple pedigrees, and further studies are needed to replicate these results and narrow down the interval harboring the underlying gene. With more information on the expression pattern of these genes in the embryonic tissues such as gonadal ridge, the selection of the candidate genes would become more accurate and help in screening of the best candidates at the earliest time. An additional factor that needs to be considered is the dosage of the genes in the interval, as illustrated by the duplication of DAX1 gene resulting in sex reversal (6). Identification of sex-determining gene(s) and establishment of the full pathway will help not only in appropriate management of cases of sex reversal/ambiguous sex, but also in understanding the molecular aspects of organogenesis.


   Acknowledgments
 
We thank G. R. Chandak for providing markers for the genome-wide scan and Chris Tyler-Smith for his valuable comments.


   Footnotes
 
This work was supported by the Council of Scientific and Industrial Research, and the Indian Council of Medical Research, Government of India, New Delhi.

Disclosure Summary: All authors have nothing to declare.

First Published Online July 25, 2006

1 S.R. and K.T. contributed equally. Back

Abbreviations: HDM, High-density marker; MDM, micro-density marker; SRY, sex-determining region on Y-chromosome.

Received May 4, 2006.

Accepted July 19, 2006.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results and Discussion
 References
 

  1. Sinclair AH, Berta P, Palmer MS, Hawkins JR, Griffiths BL, Smith MJ, Foster JW, Frischauf AM, Lovell-Badge R, Goodfellow PN 1990 A gene from the human sex-determining region encodes a protein with homology to a conserved DNA-binding motif. Nature 346:240–244[CrossRef][Medline]
  2. Foster JW, Dominguez-Steglich MA, Guioli S, Kowk G, Weller PA, Stevanovic M, Weissenbach J, Mansour S, Young ID, Goodfellow PN, Brook JD, Schaffer AJ 1994 Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene. Nature 372:525–530[CrossRef][Medline]
  3. Qin Y, Bishop CE 2005 Sox9 is sufficient for functional testis development producing fertile male mice in the absence of Sry. Hum Mol Genet 14:1221–1229[Abstract/Free Full Text]
  4. Denys P, Malvaux P, Van Den Berghe H, Tanghe W, Proesmans W 1967 Association of an anatomo-pathological syndrome of male pseudohermaphroditism, Wilms’ tumor, parenchymatous nephropathy and XX/XY mosaicism. Arch Fr Pediatr 24:729–739[Medline]
  5. Frasier SD, Bashore RA, Mosier HD 1964 Gonadoblastoma associated with pure gonadal dysgenesis in monozygous twins. J Pediatr 64:740–745[CrossRef][Medline]
  6. Bardoni B, Zanaria E, Guioli S, Floridia G, Worley KC, Tonini G, Ferrante E, Chiumello G, McCabe ER, Fraccaro M, Zuffardi O, Camerino G 1994 A dosage sensitive locus at chromosome Xp21 is involved in male to female sex reversal. Nat Genet 7:497–501[CrossRef][Medline]
  7. Achermann JC, Ito M, Ito M, Hindmarsh PC, Jameson JL 1999 A mutation in the gene encoding steroidogenic factor-1 causes XY sex reversal and adrenal failure in humans. Nat Genet 22:125–126[CrossRef][Medline]
  8. Raymond CS, Parker ED, Kettlewell JR, Brown LG, Page DC, Kusz K, Jaruzelska J, Reinberg Y, Flejter WL, Bardwell VJ, Hirsch B, Zarkower D 1999 A region of human chromosome 9p required for testis development contains two genes related to known sexual regulators. Hum Mol Genet 8:989–996[Abstract/Free Full Text]
  9. Ferguson-Smith MA, Cooke A, Affara NA, Boyd E, Tolmie JL 1990 Genotype-phenotype correlations in XX males and their bearing on current theories of sex determination. Hum Genet 84:198–202[Medline]
  10. Thangaraj K, Gupta NJ, Chakravarty B, Singh L 1998 A 47,XXY female. Lancet 352:1121
  11. Sternberg WH, Barclay DL, Kloepfer HW 1968 Familial XY gonadal dysgenesis. N Engl J Med 278:695–700[Medline]
  12. Affara NA 1991 Sex and the single Y. Bioessays 13:475–478[CrossRef][Medline]
  13. Ferguson MW, Joanen T 1982 Temperature of egg incubation determines sex in Alligator mississippiensis. Nature 296:850–853[CrossRef][Medline]
  14. Brennan J, Capel B 2004 One tissue, two fates: molecular genetic events that underlie testis versus ovary development. Nat Rev Genet 5:509–521[Medline]
  15. Bennett CP, Docherty Z, Robb SA, Ramani P, Hawkins JR, Grant D 1993 Deletion 9p and sex reversal. J Med Genet 30:518–520[Abstract]
  16. Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA, Rose EA, Kral A, Yeger H, Lewis WH, Jones C, Housman DE 1990 Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms’ tumor locus. Cell 60:509–520[CrossRef][Medline]
  17. Lala DS, Rice DA, Parker KL 1992 Steroidogenic factor I, a key regulator of steroidogenic enzyme expression, is the mouse homolog of fushi tarazu-factor I. Mol Endocrinol 6:1249–1258[Abstract]
  18. Luo X, Ikeda Y, Parker KL 1994 A cell-specific nuclear receptor is essential for adrenal and gonadal development and sexual differentiation. Cell 77:481–490[CrossRef][Medline]
  19. Espiner EA, Veale AM, Sands VE, Fitzgerald PH 1970 Familial syndrome of streak gonads and normal male karyotype in five phenotypic females. N Engl J Med 283:6–11[Medline]
  20. Boczkowski K 1976 Familial occurrence of gonadal tumors in XY females with breast development. Hum Genet 33:289–294[CrossRef][Medline]
  21. German J, Simpson JL, Chaganti RS, Summitt RL, Reid LB, Merkatz IR 1978 Genetically determined sex-reversal in 46,XY humans. Science 202:53–56[Abstract/Free Full Text]
  22. Jawaheer D, Juo SH, Le Caignec C, David A, Petit C, Gregersen P, Dowbak S, Damle A, McElreavey K, Ostrer H 2003 Mapping a gene for 46,XY gonadal dysgenesis by linkage analysis. Clin Genet 63:530–535[CrossRef][Medline]
  23. Fuqua JS, Sher ES, Fechner PY, Ostrer H, Oddeux C, Schafer AJ, Rosales TO, Migeon CJ, Berkovitz GD 1996 Linkage analysis of a kindred with inherited 46,XY partial gonadal dysgenesis. J Clin Endocrinol Metab 81:4479–4483[Abstract]
  24. Thangaraj K, Joshi MB, Reddy AG, Gupta NJ, Chakravarty B, Singh L 2002 CAG repeat expansion in the androgen receptor gene is not associated with male infertility in Indian populations. J Androl 23:815–818[Abstract/Free Full Text]
  25. Zanaria E, Muscatelli F, Bardoni B, Strom TM, Guioli S, Guo W, Lalli E, Moser C, Walker AP, McCabe ER, Meitinger T, Monaco AP, Sassone-Corsi P, Camerino G 1994 An unusual member of the nuclear hormone receptor superfamily responsible for X-linked adrenal hypoplasia congenita. Nature 372:635–641[CrossRef][Medline]
  26. Thangaraj K, Reddy AG, Singh L 2002 Is the amelogenin gene reliable for gender identification in forensic casework and prenatal diagnosis? Int J Legal Med 116:121–123[CrossRef][Medline]
  27. Thangaraj K, Singh L, Reddy AG, Rao VR, Sehgal SC, Underhill PA, Pierson M, Frame IG, Hagelberg E 2003 Genetic affinities of the Andaman Islanders, a vanishing human population. Curr Biol 13:86–93[CrossRef][Medline]
  28. Cottingham Jr RW, Idury RM, Schaffer AA 1993 Faster sequential genetic linkage computations. Am J Hum Genet 53:252–263[Medline]
  29. Mukhopadhyay N, Almasy L, Schroeder M, Mulvihill WP, Weeks DE 2005 Mega2: data-handling for facilitating genetic linkage and association analyses. Bioinformatics 21:2556–2557[Abstract/Free Full Text]
  30. Terwilliger JD, Speer M, Ott J 1993 Chromosome-based method for rapid computer simulation in human genetic linkage analysis. Genet Epidemiol 10:217–224[CrossRef][Medline]
  31. Warburton PE, Giordano J, Cheung F, Gelfand Y, Benson G 2004 Inverted repeat structure of the human genome: the X-chromosome contains a preponderance of large, highly homologous inverted repeats that contain testes genes. Genome Res 14:1861–1869[Abstract/Free Full Text]
  32. Singh BN, Suresh A, UmaPrasad G, Subramanian S, Sultana M, Goel S, Kumar S, Singh L 2003 A highly conserved human gene encoding a novel member of WD-repeat family of proteins (WDR13). Genomics 81:315–328[CrossRef][Medline]
  33. Anopriyenko OV, Zakian SM 2004 Evolution of mammalian sex chromosomes: cooperation of genetic and epigenetic factors. Genetika 40:1013–1033[Medline]



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V. Suryavathi, A. Khattri, K. Gopal, D. S. Rani, S. Panneerdoss, N. J. Gupta, B. Chakravarty, M. Deenadayal, L. Singh, and K. Thangaraj
Novel Variants in UBE2B Gene and Idiopathic Male Infertility
J Androl, September 1, 2008; 29(5): 564 - 571.
[Abstract] [Full Text] [PDF]

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M. Dumic, K. Lin-Su, N. I. Leibel, S. Ciglar, G. Vinci, R. Lasan, S. Nimkarn, J. D. Wilson, K. McElreavey, and M. I. New
Report of Fertility in a Woman with a Predominantly 46,XY Karyotype in a Family with Multiple Disorders of Sexual Development
J. Clin. Endocrinol. Metab., January 1, 2008; 93(1): 182 - 189.
[Abstract] [Full Text] [PDF]

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