Sex Reversal--Why Genetic XY Males Develop as Females

Newswise — Men may or may not come from Mars but cell biologists have known for a century that human sex determination comes from our 23rd pair of chromosomes. Those with an XX pair are female. Those with an XY pair are usually male. The exception arises in "intersex" individuals, genetic XY males who are born with reproductive organs or genitalia that do not match their sex chromosomes. No one knew what went wrong until 1990, when XY sex-reversal was traced to mutations in a region of the Y chromosome that encodes a protein named SRY. Transported at a critical moment in fetal development into the nucleus of cells that will become gonads, the normal SRY protein switches on the genes required to make the male testis. In XY individuals with mutations in SRY, male-to-female sex reversal occurs. No one knew why until now.

Some mutated SRY proteins do not "dock" correctly to proteins that mediate entry into the cell nucleus, according to Australian scientists led by David Jans at Monash University and Vincent Harley at Prince Henry's Institute of Medical Research (PHIMR). When mutated in this way, SRY proteins cannot get into the nucleus to perform their role in male gene expression. Addressing a minisymposium at the American Society for Cell Biology's 43rd Annual Meeting in San Francisco, Jans will describe their studies of mutated SRY proteins from four sex-reversed XY adults. Each mutation was different, but all affected the DNA-binding domain of SRY. Some mutations ruined the "nuclear localization signal" in SRY, whereas other patients had mutations that prevented SRY from binding to DNA, say Jans.

Besides throwing light on the mystery of XY sex-reversal, the researchers say this may be the first report of a clinical phenotype caused by the failure of a specific protein to be imported into the nucleus. How molecules get in and out of the nucleus is a hot area in cell research. Things like HIV virus that get into the nucleus, but shouldn't, can cause disease. Things that should get out, but can't, such as messenger RNA with aberrant "repeats" are implicated in several inherited neurological diseases. XY sex-reversal appears to be the first disorder linked to something that should get into the nucleus, but can't.

However, the XY sex reversal story is still incomplete, say the researchers. In their first report in the June 10th issue of PNAS, Jans and Harley describe how the SRY protein can enter the nucleus through two different pathways, both of which are important for sex determination. "We now understand how one pathway works. If SRY cannot be transported into the nucleus to perform its role, this can lead to an XY female," Jans explains. "But there is another pathway, which is also characterized by sex-reversing mutations, and which we suspect might be regulated by the calcium-binding protein, calmodulin. Our work is now focused on that second pathway."

XY sex reversal is not as rare as many imagine. In Australia, about one in 4000 newborns is sex-reversed. "This research not only helps to better understand the molecular basis of sex determination but also how things change in intersex children," says Harley. "These findings could help identify these children before birth, a diagnosis that could not only prepare expectant parents but, because intersex children are often at high risk of gonadal cancer, it could allow preventive health measures to be introduced as early as possible."

Defective Importin Beta1 Recognition and Nuclear Import of the Sex-Determining Factor SRY are Associated with XY Sex Reversing Mutations, V. R. Harley,1 S. Layfield,2 C. L. Mitchell,3 J. K. Forwood,4 A. P. John,5 L. J. Briggs,5 S. G. McDowall,2 D. A. Jans4 ; 1 Prince Henry's Institute of Medical Research, Clayton, Australia, 2 Howard Florey Institute, Parkville, Australia, 3 Cytopia Pty Ltd, Melbourne, Australia, 4 Biochemistry & Molecular Biology, Monash University, Clayton, Australia, 5 Division for Biochemistry & Molecular Biology, Australian National University, Canberra, Australia.