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Genetic Control of Sexual Differentiation in Humans

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Abstract

The current literature results on genetic control of sex differentiation and morphogenesis of the human reproductive system are reviewed. Several examples of the nosologic forms caused by mutations in the genes analyzed are considered.

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REFERENCES

  1. Swain, A. and Lovell-Badge, R., Mammalian Sex Determination: A Molecular Drama, Genes Dev., 1999, vol. 13, pp. 755-767.

    Google Scholar 

  2. Osipova, G.R., Genetics of Normal and Disturbed Sex Determination, Genetika (Moscow), 1996, vol. 32, no. 2, pp. 184-191.

    Google Scholar 

  3. Vasil'chenko, G.S., Seksopatologiya. Spravochnik (A Handbook on Sexopathology), Moscow: Meditsyna, 1990.

    Google Scholar 

  4. Falin, L.I., Embriologiya cheloveka. Atlas (Human Embryology: An Atlas), Moscow: Meditsyna, 1976.

    Google Scholar 

  5. Van Wagenen, G. and Simpson, M.E., Embryology of the Ovary and Testis in Homo sapiens and Macaca mulatta, New Haven: Yale Univ. Press, 1965.

    Google Scholar 

  6. Semenova-Tyan-Shanskaya, A.G., The Origin, Differentiation, and Migration of Gonocytes in Human Early Embryos, Abstract of Cand. Sci. (Biol.) Dissertation, Leningrad: Institute of Experimental Medicine, Russian Academy of Medical Sciences, 1973.

    Google Scholar 

  7. Kurilo, L.F., Morpho-Functional Characterization of Oogenesis in Mammals and Man, Doctoral (Biol.) Dissertation, Moscow: Kol'tsov Institute of Developmental Biology, 1985.

    Google Scholar 

  8. Bodemer, Ch.W., Modern Embryology, New York: Holt, Rinehart, and Winston, 1968.

    Google Scholar 

  9. England, M.A., A Colour Atlas of Life Before Birth: Normal Fetal Development, London: Wolfe Med., 1983.

    Google Scholar 

  10. Vorsanova, S.G., Yurov, Yu.B., and Chernyshov, V.N., Khromosomnye sindromy i anomalii. Klassifikatsiya i nomenklatura (Chromosome Syndromes and Abnormalities: Classification and Nomenclature), Rostov-on-Don, 1999.

  11. Kozlova, S.I., Demikova, N.S., Semanova, E., and Blinnikova, O.E., Nasledstvennye sindromy i mediko-geneticheskoe konsul'tirovanie (Hereditary Syndromes and Medical Genetic Counseling), Moscow: Praktika, 1996.

    Google Scholar 

  12. Kurilo, L.F., Genetically Determined Disorders of the Male Reproductive System, Seksologiya i andrologiya, Kiev, 1996, issue 3, pp. 28-43.

  13. Kurilo, L.F., A Contribution of Genetic Pathology to Misdevelopment of the Reproductive System in Patients, Seksologiya i andrologiya, Kiev, 1998, issue 4, pp. 18-27.

  14. Page, D.C., Mosher, R., Simpson, E.M., et al., The Sex-Determining Region of the Human Y Chromosome Encodes a Finger Protein, Cell (Cambridge, Mass.), 1987, vol. 51, pp. 1091-1104.

    Google Scholar 

  15. Sinclair, A.H., Berta, P., Palmer, M.S., et al., A Gene from the Human Sex-Determining Region Encodes a Protein with Homology to a Conserved DNA-Binding Motif, Nature, 1990, vol. 346, pp. 240-244.

    Google Scholar 

  16. Cameron, F. and Sinclair, A.H., Mutation in SRY and SOX9: Testis-Determining Genes, Hum. Mutat., 1997, vol. 9, pp. 388-395.

    Google Scholar 

  17. Giese, K., Cox, J., and Grosschedl, R., The HMG Domain of Lymphoid Enhancer Factor 1 Bends DNA and Facilitates Assembly of Functional Nucleoprotein Structures, Cell (Cambridge, Mass.), 1992, vol. 69, pp. 185-195.

    Google Scholar 

  18. McElreavey, K., Vilain, E., Abbas, N., et al., A Regulatory Cascade Hypothesis for Mammalian Sex Determination: SRY Represses a Negative Regulator of Male Development, Proc. Natl. Acad. Sci. USA, 1993, vol. 90, pp. 3368-3372.

    Google Scholar 

  19. McElreavey, K. and Fellous, M., Sex Determination and the Y Chromosome, Am. J. Med. Genet., 1999, vol. 89, pp. 176-185.

    Google Scholar 

  20. Ferrari, S., Harley, V.R., Pontiggia, A., et al., SRY, Like HMG1, Recognizes Sharp Angles in DNA, EMBO J., 1992, vol. 11, pp. 4497-4506.

    Google Scholar 

  21. Harley, V.R., Lovell-Badge, R., and Goodfellow, P.N., Definition of a Consensus DNA-Binding Site for SRY, Nucleic Acids Res., 1994, vol. 22, pp. 1500-1501.

    Google Scholar 

  22. Koopman, P., Gubbay, J., Vivian, N., et al., Male Development of Chromosomally Female Mice Transgenic for sry, Nature, 1991, vol. 351, pp. 117-121.

    Google Scholar 

  23. Hacker, A., Capel, B., Goodfellow, P., and Lovell-Badge, R., Expression of Sry, the Mouse Sex-Determining Gene, Development (Cambridge, UK), 1995, vol. 121, pp. 1603-1614.

    Google Scholar 

  24. Salas-Cortes, L., Jaubert, F., Barbaux, S., et al., The Human SRY Protein Is Present in Fetal and Adult Sertoli Cells and Germ Cells, Int. J. Dev. Biol., 1999, vol. 43, pp. 135-140.

    Google Scholar 

  25. Haqq, C.M., King, C.-Y., Ukiyama, E., et al., Molecular Basis of Mammalian Sexual Determination: Activation of Mullerian Inhibiting Substance Gene Expression by SRY, Science, 1994, vol. 266, pp. 1494-1500.

    Google Scholar 

  26. Pringle, M.J. and Page, D.C., Somatic and Germ Cell Sex Determination in the Developing Gonad, Infertility in the Male, Lipshultz, L.I. and Howards, S.S., Eds., St Louis: Mosby-Year Book, 1997, 3rd ed., pp. 3-22.

    Google Scholar 

  27. MacLean, H.E., Warne, G.L., and Zajac, J.D., Intersex Disorders: Shedding Light on Male Sexual Differentiation beyond SRY, Clin. Endocrinol., 1997, vol. 46, pp. 101-108.

    Google Scholar 

  28. Andrology: Male Reproductive Health and Dysfunction, Nieschlag, E. and Behre, H., Eds., Berlin: Springer-Verlag, 1997, pp. 133-159.

    Google Scholar 

  29. Cooper, C.S. and Sandlow, J.L., Azoospermia in a 46,XX/47,XXX Phenotypic Male, Urology, 1996, vol. 48, pp. 947-948.

    Google Scholar 

  30. Zanaria, E., Muscatelli, F., Bardoni, B., et al., An Unusual Member of the Nuclear Hormone Receptor Superfamily Responsible for X-Linked Adrenal Hypoplasia Congenital, Nature, 1994, vol. 372, pp. 635-641.

    Google Scholar 

  31. Bardoni, B., Zanaria, E., Guioli, S., et al., A Dosage-Sensitive Locus at Chromosome Xp21 Is Involved in Male to Female Sex Reversal, Nat. Genet., 1994, vol. 7, pp. 497-501.

    Google Scholar 

  32. Muscatelli, F., Strom, T.M., Walker, A.P., et al., Mutations in the DAX-1 Gene Rise to Both X-Linked Adrenal Hypoplasia Congenita and Hypogonadotropic Hypospadism, Nature, 1994, vol. 372, pp. 672-676.

    Google Scholar 

  33. Yanase, T., Takayanagi, R., Oba, K., et al., New Mutation of DAX-1 Genes in Two Japanese Patients with XLinked Congenital Adrenal Hypoplasia and Hypogonadotropic Hypogonadism, J. Clin. Endocrinol. Metab., 1996, vol. 81, pp. 166-176.

    Google Scholar 

  34. Swain, A., Narvaez, V., Burgoyne, P., et al., Dax1 Antagonizes Sry Action in Mammalian Sex Determination, Nature, 1998, vol. 391, pp. 761-767.

    Google Scholar 

  35. Habiby, R.L., Boepple, P., Nachtigall, L., et al., Adrenal Hypoplasia Congenital with Hypogonadotropic Hypogonadism, J. Clin. Invest., 1996, vol. 98, pp. 1055-1062.

    Google Scholar 

  36. Lalli, E., Bardoni, B., Zapopoulos, F., et al., A Transcriptional Silencing Domain in DAX-1 Whose Mutation Causes Adrenal Hypoplasia Congenita, Mol. Endocrinol., 1997, vol. 11, pp. 1950-1960.

    Google Scholar 

  37. Kletter, G.B., Gorski, J.L., and Kelch, R.P., Congenital Adrenal Hypoplasia and Isolated Gonadotropin Deficiency, Trends Endocrinol. Metab., 1991, vol. 2, pp. 123-128.

    Google Scholar 

  38. Pritchard-Jones, K., Fleming, S., Davidson, D., et al., The Candidate Wilm's Tumor Gene Is Involved in Genitourinary Development, Nature, 1990, vol. 346, pp. 194-197.

    Google Scholar 

  39. Mueller, R.F., The Denys-Drash Syndrome, J. Med. Genet., 1994, vol. 31, pp. 471-477.

    Google Scholar 

  40. Pelletier, J., Bruening, W., Kashtan, C.E., et al., Germline Mutations in the Wilm's Tumor Suppressor Gene Are Associated with Abnormal Urogenital Development in Denys-Drash Syndrome, Cell (Cambridge, Mass.), 1991, vol. 67, pp. 437-447.

    Google Scholar 

  41. Nachtigal, M.W., Hirokawa, Y., Enyeart-VanHouten, D.L., et al., Wilm's Tumor 1 and Dax-1 Modulate the Orphan Nuclear Receptor SF-1 in Sex-Specific Gene Expression, Cell (Cambridge, Mass.), 1998, vol. 93, pp. 445-454.

    Google Scholar 

  42. Kim, J., Prawitt, D., Bardeesy, N., et al., The Wilm's Tumor Suppressor Gene (Wt1) Product Regulates Dax-1 Gene Expression during Gonadal Differentiation, Mol. Cell. Biol., 1999, vol. 19, pp. 2289-2299.

    Google Scholar 

  43. Nakagama, H., Heinrich, G., Pelletier, J., and Housman, D.E., Sequence and Structural Requirements for High-Affinity DNA-Binding by the WT1 Gene Product, Mol. Cell. Biol., 1995, vol. 15, pp. 1489-1498.

    Google Scholar 

  44. Lee, S.B., Huang, K., Palmer, R., et al., The Wilm's Tumor Suppressor WT1 Encodes a Transcriptional Activator of Amphiregulin, Cell (Cambridge, Mass.), 1999, vol. 98, pp. 663-673.

    Google Scholar 

  45. Kreidberg, J.A., Sariola, H., Loring, J.M., et al., WT-1 Is Required for Early Kidney Development, Cell (Cambridge, Mass.), 1993, vol. 74, pp. 679-691.

    Google Scholar 

  46. Clemens, J.W., Lala, D.S., Parker, K.L., and Richards, J.S., Steroidogenic Factor-1 Binding and Transcriptional Activity of the Cholesterol Side-Chain Cleavage Promoter in Rat Granulosa Cells, Endocrinology, 1994, vol. 134, pp. 1499-1508.

    Google Scholar 

  47. Bakke, M. and Lund, J., Mutually Exclusive Interactions of Two Nuclear Orphan Receptors Determine Activity of a Cyclic Adenosine 3',5'-Monophosphate-Responsive Sequence in the Bovine CYP17 Gene, Mol. Endocrinol., 1995, vol. 9, pp. 327-339.

    Google Scholar 

  48. Ikeda, Y., Shen, W.H., Ingraham, H.A., and Parker, J.L., Developmental Expression of Mouse Steroidogenic Factor-1, an Essential Regulator of the Steroid Hydroxylases, Mol. Endocrinol., 1994, vol. 8, pp. 654-662.

    Google Scholar 

  49. Luo, X., Ikeda, Y., and Parker, K.L., A Cell-Specific Nuclear Receptor Is Essential for Adrenal and Gonadal Development and Sexual Differentiation, Cell (Cambridge, Mass.), 1994, vol. 77, pp. 481-490.

    Google Scholar 

  50. Shen, W.H., Moore, C.C., Ikeda, Y., et al., Nuclear Receptor Steroidogenic Factor 1 Regulates the Mullerian Inhibiting Substance Gene: A Link to the Sex Determination Cascade, Cell (Cambridge, Mass.), 1994, vol. 77, pp. 651-661.

    Google Scholar 

  51. Kent, J., Wheatley, S.C., Andrews, J.E., et al., A Male-Specific Role for SOX-9 in Vertebrate Sex Determination, Development (Cambridge, UK), 1996, vol. 122, pp. 2813-2822.

    Google Scholar 

  52. Meyer, J., Sudbeck, P., Held, M., et al., Mutational Analysis of the SOX9 Gene in Campomelic Dysplasia and Autosomal Sex Reversal: Lack of Genotype/Phenotype Correlations, Hum. Mol. Genet., 1997, vol. 6, pp. 91-98.

    Google Scholar 

  53. Wagner, T., Wirth, J., Meyer, J., et al., Autosomal Sex Reversal and Campomelic Dysplasia Are Caused by Mutations in and around the SRY-Related Gene SOX9, Cell (Cambridge, Mass.), 1994, vol. 79, pp. 1111-1120.

    Google Scholar 

  54. Josso, N., Lamarre, I., Picard, J.Y., et al., Anti-Mullerian Hormone in Early Human Development, Early Hum. Dev., 1993, vol. 33, pp. 91-99.

    Google Scholar 

  55. Faure, E., Gouerdard, L., Imbeaud, S., et al., Mutant Isoforms of the Anti-Mullerian Hormone Type II Receptor Are Not Expressed at the Cell Membrane, J. Biol. Chem., 1996, vol. 271, pp. 30 571-30 575.

    Google Scholar 

  56. Cohen-Haguenauer, O., Picard, J.Y., Mattei, M.-G., et al., Mapping of the Gene for Anti-Mullerian Hormone to the Short Arm of the Human Chromosome 19, Cytogenet. Cell Genet., 1987, vol. 44, pp. 2-6.

    Google Scholar 

  57. Behringer, R.R., Finegold, M.J., and Cate, R.L., Mullerian-Inhibiting Substance Function during Mammalian Sexual Development, Cell (Cambridge, Mass.), 1994, vol. 79, pp. 415-425.

    Google Scholar 

  58. Mishina, Y., Rey, R., Finegold, M.J., et al., Genetic Analysis of the Mullerian-Inhibiting Substance Signal Transduction Pathway in Mammalian Sexual Differentiation, Genes Dev., 1996, vol. 10, pp. 2577-2587.

    Google Scholar 

  59. Viger, R.S., Mertineit, C., Trasler, J.M., and Nemer, M., Transcription Factor GATA-4 Is Expressed in a Sexually Dimorphic Pattern during Mouse Gonadal Development and Is a Potent Activator of the Mullerian-Inhibiting Substance Promoter, Development (Cambridge, UK), 1998, vol. 125, pp. 2665-2675.

    Google Scholar 

  60. De Santa, P., Bonneaud, N., Boizet, B., et al., Direct Interaction of SRY-Related Protein SOX9 and Steroidogenic Factor 1 Regulates Transcription of the Human Anti-Mullerian Hormone Gene, Mol. Cell Biol., 1998, vol. 18, pp. 6653-6665.

    Google Scholar 

  61. Tremblay, J.J. and Viger, R.S., Transcriptional Factor GATA-4 Enhances Mullerian-Inhibiting Substance Gene through a Direct Interaction with SF-1, Mol. Endocrinol., 1999, vol. 13, pp. 1388-1401.

    Google Scholar 

  62. Fujii, T., Pichel, J.G., Taira, M., et al., Expression Patterns of the Murine LIM Class Homeobox Gene lim1 in the Developing Brain and Excretory System, Dev. Dyn., 1994, vol. 199, pp. 73-83.

    Google Scholar 

  63. Torres, M., Gomes-Pardo, E., Dressler, G.R., and Gruss, P., Pax-2 Controls Multiple Steps of Urogenital Development, Development (Cambridge, UK), 1995, vol. 12, pp. 4057-4065.

    Google Scholar 

  64. Bidgood, M.J., Shen, L., and McMahon, A.P., Sertoli Cell Signaling by Desert Hedgehog Regulates the Male Germ Line, Curr. Biol., 1996, vol. 6, pp. 298-304.

    Google Scholar 

  65. Vainio, S., Heikkila, M., Kispert, A., et al., Female Development in Mammals Is Regulated by Wnt-4 Signaling, Nature, 1999, vol. 397, pp. 405-500.

    Google Scholar 

  66. Slavotinek, A., Schwarz, C., Getty, J.F., et al., Two Cases with Interstitial Deletions of Chromosome 2 and Sex Reversal in One, Am. J. Med. Genet., 1999, vol. 86, pp. 75-81.

    Google Scholar 

  67. Bennett, C.P., Docherty, Z., Robb, S.A., et al., Deletion 9p and Sex Reversal, J. Med. Genet., 1993, vol. 30, pp. 518-520.

    Google Scholar 

  68. Veitia, R., Nunes, M., Rapport, R., et al., Swyers Syndrome and 46,XY Partial Gonadal Dysgenesis Associated with 9p Deletions and Absence of Monosomy 9p Syndrome, Am. J. Hum. Genet., 1998, vol. 63, pp. 901-904.

    Google Scholar 

  69. Wilkie, A.O., Campbell, F.M., Daubeney, P., et al., Complete and Partial XY Sex Reversal Associated with Terminal Deletion of 10q: Report of 2 Cases and Literature Review, Am. J. Med. Genet., 1993, vol. 46, pp. 597-600.

    Google Scholar 

  70. Waggoner, D.J., Chow, C.K., Dowton, S.B., and Watson, M.S., Partial Monosomy of Distal 10q: Three New Cases and a Review, Am. J. Med. Genet., 1999, vol. 86, pp. 1-5.

    Google Scholar 

  71. Smith, G.A., McClive, P.J., Western, P.S., et al., Conservation of a Sex-Determining Gene, Nature, 1999, vol. 402, pp. 601-602.

    Google Scholar 

  72. Chillon, M., Casals, T., Mercier, B., et al., Mutations in the Cystic Fibrosis Gene in the Patients with Congenital Absence of the Vas Deferens, N. Engl. J. Med., 1995, vol. 332, pp. 1475-1480.

    Google Scholar 

  73. Kolchanov, N.A., Anan'ko, E.A., Kolpakov, F.A., et al., Gene Networks, Mol. Biol. (Moscow), 2000, vol. 34, no. 4, pp. 533-544.

    Google Scholar 

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Chernykh, V.B., Kurilo, L.F. Genetic Control of Sexual Differentiation in Humans. Russian Journal of Genetics 37, 1103–1114 (2001). https://doi.org/10.1023/A:1012390418656

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