A group of researchers from Case Western Reserve University School of Medicine have completed a comprehensive molecular analysis of a toddler who developed as a female despite having a male genetic background, termed XY sex reversal. The study identifies for the first time how the machinery for destruction of proteins can render a person poised at the borderline between male and female patterns of development.
The toddler in the study had a mutation in the gene encoding SRY, or sex-determining region of the Y chromosome, a protein that initiates testes development in embryos. Mutations in SRY have previously been found that impair the protein's ability to attach to DNA and activate specific genes involved in sex determination. Many mutations have been found at the front surface of SRY, which contacts specific sites in the DNA of chromosomes. Such impairment prevents testes development, leading to a mismatch between a child's chromosomal sex (XY, ordinarily male) and outward features (female). This mismatch (designated XY sex reversal) prevents the formation of either testes or functional ovaries, a condition often associated with gonadoblastoma, a rare form of cancer.
The new analysis is unusual in that the toddler's SRY, containing a mutation on the back surface of the protein, binds and bends DNA normally. Further, the child's father and paternal uncle had the same mutation, but did not experience any issues related to testes development or fertility. Her two brothers also have the mutation but no issues related to testes development. The mutation in this case can be compatible either with male or female development, presumably due to other genes or chance events.
Why was the child female? To solve this mystery, the researchers examined the susceptibility of the variant SRY to destruction by the "proteasome," a universal molecular machine in the cells of animals and plants that destroys proteins. The signal for such destruction is provided by attachment of a small ubiquitous protein tag, called ubiquitin. The discovery of ubiquitin and its role in flagging proteins for proteasomal destruction led to the 2004 Nobel Prize in Chemistry to American biochemist Irwin Rose and Israeli scientists Aaron Ciechanover and Avram Hershko.
Weiss and his team discovered the mutation of the back surface of SRY increased ubiquitin tagging and so accelerated destruction by the proteasome. Regulation of male development thus rose or fell with the remaining number of SRY molecules in each cell that escaped destruction. This appears to be the first example of how the ubiquitin tagging mechanism found by Rose, Ciechanover, and Hershko is responsible for rendering a genetic switch ambiguous in a human embryo (or any other animal).
"This case report was remarkable for both the family details and the molecular aspects," said Michael Weiss, M.D., Ph.D., M.B.A, and Chairman of the Department of Biochemistry at Case Western Reserve School of Medicine. "The family tree was unusually complete, with genotyping of the siblings, father and uncle. The daughter's gonads were also examined after surgery and exhibited an early form of gonadal cancer. Surprisingly, no one seems to have studied this family or their interesting mutation from a biophysical perspective or toward the goal of how the mutation might affect the gene-regulatory properties of SRY."
Weiss and his research team, including Drs. Joseph Racca, Yen-Shan Chen, Yanwu Yang, and Nelson Phillips, all of Case Western Reserve University School of Medicine, performed biochemical and cell-based experiments to understand how the toddler's variant SRY interacted with DNA target sites and with male-specific genes.
Said Weiss, "How this child developed in the womb represented a race between proteasome destruction and DNA-based gene regulation." For this girl with XY chromosomes, the proteasome won.
The study highlights the tenuous steps in embryonic development related to sex determination and how a single genetic mutation can mean the difference between male and female. The toddler and her family represent an important genetic aberration, providing a scientific rationale for sexual ambiguity. According to Weiss, the study "shows that the finding the right patient can be enormously informative for basic science."
The unprecedented 24-page investigation was published in the Journal of Biological Chemistry. It was later featured in the journal Biology of Reproduction.
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