Sex and the single DAX1: too little is bad, but can we have too much?

E R McCabe

J Clin Invest. 1996;98(4):881-882. https://doi.org/10.1172/JCI118868.

Editorial

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Sex and the Single DAX1: Too Little Is Bad, But Can We Have Too Much? Editorial

Habiby et al. (1) resolve a controversy concerning develop- mRNA from human and pituitary, (11) obser- ment of male sexual characteristics, in the process opening sig- vations that have been confirmed in the mouse (12). nificant new areas for investigation. Their results indicate that If absence of functional DAX1 in males leads to HH, have the relationship between the hypothalamus and pituitary in any problems been associated with over-expression of this male sexual development may be more complex than previ- ? DAX1 maps to the 160-kb dosage-sensitive sex reversal ously appreciated, and highlight significant issues regarding (DSS) critical region in Xp21, (13) and, since the gene product the role of the DAX1 gene product in female sexual differenti- is a putative , DAX1 is a candidate for the ation. DSS gene. Patients with DSS have tandem duplications of The DAX1 gene (Dosage sensitive sex reversal - Adrenal Xp21 containing the DSS critical region, and, hence, the sec- hypoplasia congenita gene on the X , gene 1) was ond copy of the gene is not subject to X inactivation. XX fe- identified by positional cloning strategies after localization of males with DSS duplications have normal phenotypes and nor- the gene using DNA samples from patients with Xp21 contigu- mal fertility. XY genotypic males with DSS duplications and ous gene syndromes that included adrenal hypoplasia congen- normal SRY have female or ambiguous genitalia. Whether the ita (AHC) (2, 3). Observation of intragenic DAX1 mutations DAX1 gene or another gene in this portion of Xp21 is respon- in patients with AHC and hypogonadotropic hypogonadism sible for DSS remains to be determined. (HH) clarified an earlier controversy: AHC and HH were due The mouse may serve as a model for the investigation of to alteration of a single gene product and were not due to dele- DSS. The region of the contiguous to DAX1 is tion of two discrete, contiguous loci (2–4). The role of DAX1 syntenic between human and mouse (14). Therefore, if trans- in adrenal and pubertal development was all the more intrigu- genic mice expressing multiple copies of this genomic region ing because of the similarity of the carboxy-terminal portion of have a DSS phenotype, they will permit molecular genetic dis- the DAX1 protein with other nuclear hormone su- section of this region to determine whether DAX1 and DSS perfamily members. are identical, or whether another gene in the region is respon- Since DAX1 maps to a region of the X chromosome that sible for DSS. undergoes inactivation, a single copy is expressed in normal The mechanism by which DAX1 ensures normal adrenal males and females. Loss of the DAX1 gene product by dele- cortical and pubertal development remains to be determined. tion or point mutation results in developmental abnormalities The sequence similarity with other members of this transcrip- in the hypothalamic-pituitary-adrenal-gonadal axis. Results of tion factor superfamily resides in the carboxy-terminal half of previous clinical studies of HH in patients with AHC were the protein. While similarity in the amino-terminal half is not mixed regarding hypothalamic and/or pituitary origin (5–10). significant compared with most other family members, cys- Some affected boys responded to pulsatile GnRH, others did teines are arranged consistent with two zinc fingers, a struc- not. Habiby et al. investigated two families with AHC and HH, tural motif important to many other members of the superfam- and both had frameshift mutations in DAX1. Abnormal pat- ily. The murine homologue of DAX1, Ahch, has each of these terns of baseline gonadotropin levels were different in a post- cysteines conserved, despite variability in the residues sur- pubertal male in both families. One had no response to pulsa- rounding the cysteines, (12, 14) suggesting their functional im- tile GnRH and testosterone only rose to 39 ng/dl at the end of portance. one week of treatment, a result interpreted by previous au- A new orphan receptor, the short heterodimeric partner thors as a primary pituitary defect. The affected individual (SHP), has been identified and has its closest sequence similar- from the other pedigree responded normally to the initial ity with DAX1 (15). Like DAX1, SHP has an unusual amino- pulse on day 1, with minimal responses on subsequent days, terminal portion, and it is much shorter in SHP. The DAX1 but a gradual rise in testosterone to 241 ng/d1 during the week. protein has three and a half repetitions of an amino acid se-

These results indicated that he did not have absolute hypogo- quence in the NH2-terminal portion and this portion of the nadotropic hypogonadism and suggested a mixed hypotha- SHP protein has similarity with the repeat motifs, but is only a lamic/pituitary defect. Investigations, carried out with identical single repeat in length. The SHP protein appears to het- clinical protocols on patients with very similar mutations, illus- erodimerize with other transcription factors to modulate their trate the marked phenotypic heterogeneity in this disorder. activity. They show that DAX1 acts at both pituitary and hypothalamic Perhaps DAX1 has properties similar to SHP, and, there- levels to mediate pubertal development, resolving differences fore, it may be the concentration of the DAX1 protein relative in previous studies. to its heterodimeric partners that influences its activity. Loss of Conclusions from these clinical investigations are sup- DAX1 results in AHC and HH, and increased DAX1 leads to ported by studies of DAX1 . Guo et al. ob- DSS and a female phenotype or ambiguous genitalia in XY ge- served amplification of DAX1 after reverse transcription of notypic males. DAX1 definitely is involved in male sexual de- velopment, because if there is too little then the patient has HH. Too much DAX1 may have a significant impact on the determination of phenotypic sex. J. Clin. Invest. © The American Society for Clinical Investigation, Inc. Edward R.B. McCabe 0021-9738/96/08/0881/02 $2.00 Department of Pediatrics Volume 98, Number 4, August 1996, 881–882 UCLA School of Medicine

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References hypoplasia and hypogonadotropic hypogonadism by pulsatile administration of low-dose gonadotropin-releasing hormone. Acta Endocrinol. 114:153–160. 8. Bovet, P., M.J. Reymond, F. Rey, and F. Gomez. 1988. Lack of gonadotro- 1. Habiby, R.L., P. Boepple, L. Nachtigall, P.M. Sluss, W.F. Crowley, Jr., pic response to pulsatile gonadotropin-releasing hormone in isolated hypogo- and J.L. Jameson. 1996. Adrenal hypoplasia congenita with hypogonadotropic nadotropic hypogonadism associated to congenital adrenal hypoplasia. J. Endo- hypogonadism: evidence that DAX-1 mutations lead to combined hypotha- crinol. Invest lamic and pituitary defects in gonadotropin production. J. Clin. Invest. 98:1055– . 11:201–204. 1062. 9. Partsch, C.J., and W.G. Sippell. 1989. Hypothalamic hypogonadism in 2. Zanaria, E., F. Muscatelli, B. Bardoni, T.M. Strom, S. Guioli, W. Guo, E. congenital adrenal hypoplasia. Horm. Metab. Res. 21:623–625. Lalli, C. Moser, A.P. Walker, E.R.B. McCabe, T. Meitinger, A.P. Monaco, P. 10. Kletter, G.B., J.L. Gorski, and R.P. Kelch. 1991. Congenital adrenal hy- Sassone-Corsi, and G. Camerino. 1994. A novel and unusual member of the nu- poplasia and isolated gonadotropin deficiency. Trends Endocrinol. Metab. 2: clear superfamily is responsible for X-linked adrenal hypo- 123–128. plasia congenita. Nature (Lond.). 372:635–641. 11. Guo, W, T.P. Burris, and E.R.B. McCabe. 1995. Expression of DAX-1, 3. Guo, W., J.S. Mason, C.G. Stone, S.A. Morgan, S.I. Madu, A. Baldini, the gene responsible for X-linked adrenal hypoplasia congenita and hypogona- E.A. Lindsay, L.G. Biesecker, K.C. Copeland, M.N.B. Horlick, A.L. Pettigrew, dotropic hypogonadism, in the hypothalmic-pituitary-adrenal/gonadal axis. E. Zanaria, and E.R.B. McCabe. 1995. Diagnosis of X-linked adrenal hypopla- Biochem. Mol. Med. 56:8–13. sia congenita by mutation analysis of the DAX-1 gene. JAMA. 274:324–330. 12. Swain, A., E. Zanaria, A. Hacker, R. Lovell-Badger, and G. Camerino. 4. Muscatelli, F., T.M. Strom, A.P. Walker, E. Zanaria, D. Recam, A. 1996. Mouse DAX1 expression is consistent with a role in sex determination as Meindl, B. Bardoni, S. Guioli, G. Zehetner, W. Rabl, H.P. Schwartz, J.C. Ka- well as in adrenal and hypothalamus function. Nature Genetics. 12:404–409. plan, G. Camerino, T. Meitinger and A.P. Monaco. 1994. Mutations in the 13. Bardoni, B., E. Zanaria, S. Guioli, G. Floridia, K. Worley, S. Tonini, S. DAX1 gene give rise to both X-linked adrenal hypoplasia congenita and hypo- Ferrante, S. Chiumello, E.R.B. McCabe, M. Fraccaro, O. Zuffardi, and G. gonadotropic hypogonadism. Nature (Lond.). 372:672–676. Camerino. 1994. A dosage sensitive locus at Xp21 is involved in male to female 5. Gordon, D., H.N. Cohen, G.H. Beastall, I.D. Hay, and J.A. Thomson. sex reversal. Nature Genetics. 7:497–501. 1984. Contrasting effects of subcutaneous pulsatile GnRH therapy in congeni- 14. Guo, W., R.S. Lovell, Y.-H. Zhang, B.-L. Huang, T.P. Burris, W.J. tal adrenal hypoplasia and Kallmann’s syndrome. Clin. Endocrinol. 21:597–603. Craigen, and E.R.B. McCabe. 1996. Ahch, the mouse homologue of DAX1: 6. Kruse, K., W.G. Sippell, and K.V. Schnakenburg. 1984. Hypogonadism in cloning, characterization and synteny with GyK, the glycerol kinase locus. congenital adrenal hypoplasia: Evidence for a hypothalamic origin. J. Clin. En- Gene. In Press. docrinol. Metab. 58:12–17. 15. Seol, W., H.-S. Choi, and D.D. Moore. 1996. An orphan nuclear hor- 7. Kikuchi, K., M. Kaji, T. Momoi, H. Mikawa, Y. Shigematsu, and M. mone receptor that lacks a DNA binding domain and heterodimerizes with Sudo. 1987. Failure to induce puberty in a man with X-linked congenital adrenal other receptors. Science (Wash. DC). 272:1336–1339.

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