Summary
The syndrome of 46,XX true hermaphroditism is a clinical condition in which both ovarian and testicular tissue are found in one individual. Both Mullerian and Wolffian structures are usually present, and external genitalia are often ambiguous. Two alternative mechanisms have been proposed to explain the development of testicular tissue in these subjects: (1) translocation of chromosomal material encoding the testicular determination factor (TDF) from the Y to the X chromosome or to an autosome, or (2) an autosomal dominant mutation that permits testicular determination in the absence of TDF. We have investigated five subjects with 46,XX true hermaphroditism. Four individuals had a normal 46,XX karyotype; one subject (307) had an apparent terminal deletion of the short arm of one X chromosome. Genomic DNA was isolated from these individuals and subjected to Southern blot analysis. Only subject 307 had Y chromosomal sequences that included the pseudoautosomal boundary, SRY (sex-determining region of Y), ZFY (Y gene encoding a zinc finger protein), and DXYS5 (an anonymous locus on the distal short arm of Y) but lacked sequences for DYZ5 (proximal short arm of Y) and for the long arm probes DYZ1 and DYZ2. The genomic DNA of the other four subjects lacked detectable Y chromosomal sequences when assayed either by Southern blotting or after polymerase chain reaction amplification. Our data demonstrate that 46,XX true hermaphroditism is a genetically heterogeneous condition, some subjects having TDF sequences but most not. The 46,XX subjects without SRY may have a mutation of an autosomal gene that permits testicular determination in the absence of TDF.
Similar content being viewed by others
References
Abbas NE, Toublanc JE, Boucekkine C, Toublanc M, Affara NA, Job J-C, Fellous M (1990) A possible common origin of “Y-negative” human XX males and XX true hermaphrodites. Hum Genet 84:356–360
Berkovitz GD, Rock JA, Urban MD, Migeon CJ (1982) True hermaphroditism. Johns Hopkins Med J 151:290–297
Bernstein R, Koo GC, Wachtel SS (1980) Abnormality of the X chromosome in human 46,XY female siblings with dysgenetic ovaries. Science 207:768–769
Berta P, Hawkins JR, Sinclair AH, Taylor A, Griffiths BL, Goodfellow PN, Fellous M (1990) Genetic evidence equating SRY and the testis-determining factor. Nature 348:448–450
Chapelle A de la (1987) The Y-chromosomal and autosomal testis-determining genes. Development 101 [Suppl]:33–38
Chen H, Cutley L (1991) Molecular studies of Y chromosome using polymerase chain reaction (PCR). Pediatr Res 29:128A
Damiani D, Billerbeck AEC, Goldberg ACK, Setian N, Fellous M, Kalil J (1990) Investigation of the ZFY gene in XX true hermaphroditism and Swyer syndrome. Hum Genet 85:85–88
Disteche CM, Brown L, Saal H, Friedman C, Thuline HC, Hoar DI, Pagon RA, Page DC (1986) Molecular detection of a translocation (Y;15) in a 45,X male. Hum Genet 74:372–377
Donohoue PA, Van Dop C, McLean RH, White PC, Jospe N, Migeon CJ (1986) Gene conversion in salt-losing congenital adrenal hyperplasia with absent complement C4B protein. J Clin Endocrinol Metab 62:995–1002
Eicher EM, Beamer WG, Washburn LL, Whitten WR (1980) A cytogenetic investigation of inherited true hermaphroditism in BALB/cwt mice. Cytogenet Cell Genet 28:104–115
Ellis NA, Goodfellow PJ, Pym B, Smith M, Palmer M, Frischauf A-M, Goodfellow PN (1989) The pseudoautosomal boundary in man is defined by an Alu repeat sequence inserted on the Y chromosome. Nature 337:81–84
Espiner EA, Veale AMO, 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
Feinberg AP, Vogelstein B (1982) A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem 132:6–13
Ferguson-Smith MA (1966) X-Y chromosomal interchange in the aetiology of true hermaphroditism and of XX Klinefelter's syndrome. Lancet II:1953–1956
Ferguson-Smith MA, Cooke A, Affara NA, Boyd E, Tolmie JL (1990a) Genotype-phenotype correlations in XX males and the bearing on current theories of sex determination. Hum Genet 84:198–202
Ferguson-Smith MA, North MA, Affara NA, Briggs H (1990b) The secret of sex. Lancet 336:809–810
Ford CE, Miller OJ, Polani PE, Alemeida JC de, Briggs JH (1959) A sex-chromosome anomaly in a case of gonadal dysgenesis (Turner syndrome). Lancet I:711
Geldwerth D, Bishop C, Guellaen G, Koenig M, Vergnaud G, Mandel J-L, Weissenbach JC (1985) Extensive DNA sequence homologies between the human Y and the long arm of the X chromosome. EMBO J 4:1739–1743
German J, Simpson JL, Chaganti RSK, Summitt RL, Reid LB, Merkatz IR (1978) Genetically determined sex-reversal in 46,XY humans. Science 202:53–56
Gessler M, Thomas GH, Couillin P, Junien C, McGillivray BC, Hayden M, Jaschek G, Bruns GAP (1989) A deletion map of the WAGR region of chromosome 11. Am J Hum Genet 44:486–495
Hall BD, Spranger NW (1980) Campomelic dysplasia: further elucidation of a distinct entity. Am J Dis Child 134:285–289
Jacobs PA (1969) The chromosomal basis of some types of intersexuality in man. J Reprod Fertil 7 [Suppl]:73–78
Jacobs PA, Strong JA (1959) A case of human intersexuality having a possible XXY sex-determining mechanism. Nature 183:302–303
Jager RJ, Anvret M, Hall K, Scherer G (1990a) A human XY female with a frame shift mutation in the candidate testis-determining gene SRY. Nature 348:452–454
Jager RJ, Ebensperger C, Fraccaro M, Scherer G (1990b) A ZFY-negative 46,XX true hermaphrodite is positive for the Y pseudoautosomal boundary. Hum Genet 85:666–668
Koopman P, Muslerberg A, Capel B, Vivian N, Lovell-Badge R (1990) Expression of a candidate sex-determining gene during mouse testis determination. Nature 348:450–452
Koopman P, Gubbay J, Vivian N, Goodfellow P, Lovell-Badge R (1991) Male development of chromosomally female mice transgenic for SRY. Nature 351:117–121
Lyons J (1990) Analysis of ras gene point mutations by PCR and oligonucleotide hybridization. In: Innis MA, Gelfand DM, Shinsky JJ, White TJ (eds) PCR protocols: a guide to methods and applications. Academic Press, San Diego, pp 386–391
Migeon BR, Axelman J, Stetten G (1988) Clonal evolution in human lymphoblast cultures. Am J Hum Genet 42:742–747
Muller U, Donion T, Schmid M, Fitch N, Richer C-L, Lalande M, Latt SA (1986) Deletion mapping of the testis-determining locus with DNA probes in 46,XX males and in 46,XY and 46X,dic(Y) females. Nucleic Acids Res 14:6489–6505
Muller U, Donlon TA, Kunkel SM, Lalande M, Latt SA (1987) Y-190, a DNA probe for the sensitive detection of Y derived marker chromosomes and mosaicism. Hum Genet 75:109–113
Niekerk WA van (1981) True hermaphroditism. In: Josso N (eds) The intersex child. Karger, Basel, pp 80–99
Page DC, Brown LG, Chapelle A de la (1987a) Exchange of terminal portions of X and Y chromosomal short arms in human XX males. Nature 328:437–440
Page DC, Mosher R, Simpson EM, Fisher EMC, Mardon G, Pollack J, McGillivray B, Chapelle A de la, Brown LG (1987b) The sex-determining region of the human Y chromosome. Cell 51:1091–1104
Pai GS, Thomas GH (1980) A new R-banding technique in clinical cytogenetics. Hum Genet 54:41–45
Palmer MS, Sinclair AH, Berta P, Ellis NA, Goodfellow PN, Abbas NE, Fellous M (1989) Genetic evidence that ZFY is not the testis-determining factor. Nature 342:937–939
Petit C, Chapelle A de la, Levilliers J, Castillo S, Noel B, Weissenbach J (1987) An abnormal terminal X-Y interchange accounts for most but not all cases of human XX maleness. Cell 49:595–602
Raine J, Robertson ME, Malcolm S, Hoey H, Grant DB (1989) Absence of Y specific DNA sequences in two siblings with 46,XX hermaphroditism. Arch Dis Child 64:1185–1187
Ramsay M, Bernstein R, Zware E, Page DC, Jenkins T (1988) XX true hermaphroditism in Southern African Blacks: an enigma of primary sexual differentiation. Am J Hum Genet 43:4–13
Rouyer F, Simmler M-C, Page DC, Weissenbach J (1987) A sex chromosome rearrangement in a human XX male caused by Alu-Alu recombination. Cell 51:417–425
Sambrook J, Fritsch EF, Maniatis T (1989) Molecular cloning: a laboratory manual, 2nd edn. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY
Sinclair AH, Berta P, Palmer MS, Hawkins JR, Griffiths BL, Smith MJ, Foster JW, Frischauf AM, Lovell-Badge R, Good-fellow 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
Smith KD, Young KE, Talbot CC Jr, Schmeckpeper BJ (1987) Repeated DNA of the human Y chromosome. Development 101 [Suppl]:77–92
Vernaud G, Page DC, Simmler MC, Brown L, Rouyer F, Noel B, Botstein D, Chapelle A de la, Weissenbach J (1986) A deletion map of the human Y chromosome based on DNA hybridization. Am J Hum Genet 38:109–124
Waibel F, Scherer G, Fraccaro M, Hustinx TWJ, Weissenbach J, Wieland J, Meyerova A, Back E, Wolf U (1987) Absence of Y specific DNA sequences in human 46,XX true hermaphrodites and in 45,X mixed gonadal dysgenesis. Hum Genet 76:332–336
Washburn LL, Eicher EM (1983) Sex reversal in XY caused by dominant mutation on chromosome 17. Nature 303:338–340
Weissenbach J, Goodfellow PN, Smith KD (1989) Report of the committee on the genetic constitution of the Y chromosome. Cytogenet Cell Genet 51:438–449
Welshons WJ, Russel LB (1959) The Y chromosome as the bearer of male determining factors in the mouse. Proc Natl Acad Sci USA 45:560–566
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Berkovitz, G.D., Fechner, P.Y., Marcantonio, S.M. et al. The role of the sex-determining region of the Y chromosome (SRY) in the etiology of 46,XX true hermaphroditism. Hum Genet 88, 411–416 (1992). https://doi.org/10.1007/BF00215675
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF00215675