Genetics of Sex Determination
Harry Ostrer, M.D., Carole Oddoux, Ph.D., NYU School of Medicine
In humans and other mammals, sex determination generally proceeds in the direction of female development unless genes involved in testis determination are activated. The SRY gene (for "sex-determining region Y") is believed to be the switch that initiates the testis development.
Deregulation of the sex pathway leads to abnormal sex differentiation and, in some cases, to complete sex reversal (genetic sex of one type, chromosomal sex of the opposite type).
The identification and cloning of sex-determining genes depends on the investigation of patients with sex reversal syndromes, some with chromosomal rearrangements.
In addition to SRY, autosomal and X-linked loci have also been linked with failure to develop a testis and thus, sex reversal (table).
| Genes Involved in Male Sexual Development | |||
|---|---|---|---|
| Gene | Chromosomal Region | Associated syndrome when mutated (m) or duplicated (D) | OMIM Number |
| SRY | Yp11 | 46,XY gonadal dysgenesis, Swyer syndrome (M) | 480000 |
| SF1 | 9q33 | 46,XY gonadal dysgenesis with adrenal failure | 184757 |
| WT1 | 11p15 | Denys-Drash syndrome Frasier syndrome (M) | 194070 |
| SOX9 | 17q25 | Campomelic dysplasia (M) | 114290 |
| DAX1 | Xp21 | Dosage-sensitive sex reversal (D) | 300018 |
| XH2 | Xq13 | Alpha-thalassemia/mental retardation syndrome (M) | 300032 |
| LHX9 | 1q31-q32 | Gonadal agenesis (M) | 606066 |
| EMX2 | 10q26.1 | Gonadal agenesis (M) | 600035 |
| FGF9 | 13q11-q12 | 46,XY gonadal dysgenesis (M) | 600921 |
| M33 | 17q25 | 46,XY gonadal dysgenesis (M) | 602770 |
| GATA4 | 8p23.1-p22 | 46,XY gonadal dysgenesis (M) | 600576 |
| FOG2 | 8q23 | Gonadal dysgenesis (M) | 603693 |
| IRRR | 1q 21-q23 | 46,XY gonadal dysgenesis (M) | 147671 |
| IR | 1q 25-q26 | 46,XY gonadal dysgenesis (M) | 246200 |
| IGPRI | 19p13-2 | 46,XY gonadal dysgenesis (M) | 147370 |
| WNT4 | 1p 36.23-35 | 46,XY gonadal dysgenesis (D) | 603490 |
| FOX62 | 3q22.3 | 46,XY gonadal dysgenesis (M) | 605597 |
| DMRTI | 9p24.3 | 46,XY gonadal dysgenesis (D) | 602424 |
| IHXI | 11p12-p13 | 46,XY gonadal dysgenesis (M) | 601999 |
| DHH | 12q12-q13.1 | 46,XY gonadal dysgenesis (M) | 605423 |
Testis-determining genes are expressed in the developing gonad at the time of testis-determination. The expression of these genes can be detected by in situ hybridization or immunocytochemistry.
Genetic testing may be a useful aid for diagnosis, treatment and genetic counseling in cases of sex reversal. This should be considered once life-threatening conditions, such as congenital adrenal hyperplasia and adrenal hypoplasia congenita, have been excluded. Analysis is performed by PCR amplification of genomic DNA and, where appropriate, DNA sequencing. In some cases histological studies and participation of other family members may be helpful. Testing is provided for qualified patients and without charge for:
- 46,XX maleness
- 46,XY gonadal dysgenesis (including Swyer syndrome)
- 46,XX true hermaphroditism
For more information about genetic testing, contact:
Harry Ostrer, M.D. / Carole Oddoux, Ph.D.
Professor of Pediatrics, Pathology and Medicine
Director, Human Genetics Program
New York University School of Medicine
550 First Avenue, MSB 136
New York, NY 10016
Phone: 212-263-7596
Fax: 212-263-3477
New genes can be discovered by linkage analysis and positional cloning in familial cases of sex reversal. Typically, these present with multiple family members affected with 46,XY pure gonadal dysgenesis, 46,XY partial gonadal dysgenesis, 46,XX maleness and/or true hermaphroditism, or gonadal agenesis such as this family with multiple cases of complete partial gonadal dysgenesis. In this family, the gene was mapped to the proximal long arm of chromosome 5 using linkage analysis.
New genes can also be discovered by deletion mapping using comparative genomic hybridization in sporadic and familial cases of sex reversal and by mapping deletion breakpoints in cases with balanced translocations.
This family had multiple cases of gonadal dysgenesis with a sub-microscopic duplication on the short arm of chromosome 16.
For more information about linkage analysis and comparative genomic hybridization, contact:
Harry Ostrer, M.D.
Human Genetics Program, MSB 136
NYU School of Medicine
550 First Avenue
New York, NY 10016
Phone: 212-263-7596
Fax: 212-263-7590
Barbaux S, Niaudet P, Gubler MC, Grunfeld JP, Jaubert F, Kuttenn F, Fekete CN, Souleyreau-Therville N, Thibaud E, Fellous M, McElreavey K. Donor splice-site mutations in WT1 are responsible for Frasier syndrome. Nat Genet. 1997, 17:467-470.
Fuqua JS, Sher ES, Fechner PY, Ostrer H, Oddoux C, Schafer AJ, Rosales TO, Migeon CJ, and Berkovitz GD. Linkage analysis of a kindred with inherited 46, XY partial gonadal dysgenesis. J Clin Endocrin Metab 1996; 81:4479-4483.
Hanley NA, Hagan DM, Clement-Jones M, Ball SG, Strachan T, Salas L, McElreavey K, Robson S, Bullen P, Ostrer H, Wilson DI. Human-mouse differences in SRY, SOX9, and DAX1 expression patterns during sex determination provide novel insights into associated human sex reversal phenotypes. Mech Devel, 2000; 91:403-407.
Jawaheer D, Juo SH, Le Caignec C, David A, Petit C, Gregersen P, Dowbak S, Damle A, McElreavey K, Ostrer H. Mapping a gene for 46,XY gonadal dysgenesis by linkage analysis. Clin Genet. 2003 Jun;63:530-5.
McElreavey K, Fellous M.. Sex determination and the Y chromosome. Am J Med Genet. 1999, 89:176-185.
Sarafoglou K, Ostrer H. Familial sex reversal: A review. J Clin Endocrin Metab, 2000; 85:483-493.
Ortenberg J, Oddoux C, Craver R, McElreavey K, Salas-Cortes L, Guillen-Navarro E, Ostrer H, Sarafoglou K, Clarke V, Yee H. SRY gene expression in the ovotestes of XX true hermaphrodites. J Urol. 2002;167:1828-31.
Ostrer H. Alterations of sex differentiation in males: from candidate genes to diagnosis and treatments. Curr Pharm Des. 2004;10:501-11.
Teebi AS, Miller S, Ostrer H, Eydoux P, Colomb-Brockmann C, Oudjhane K, Watters G. Spastic paraplegia, optic atrophy, microcephaly with normal intelligence, and XY sex reversal: a new autosomal recessive syndrome? J Med Genet 1998; 35:759-762.
Veitia R, Ion A, Barbaux S, Jobling MA, Souleyreau N, Ennis K, Ostrer H, Tosi M, Meo T, Chibani J, Fellous M, McElreavey K. Mutations and sequence variants in the testis-determining region of the Y chromosome in individuals with a 46,XY female phenotype. Hum Genet. 1997; 99:648-52
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