In a recent study conducted by Case Western Reserve University School of Medicine, researchers find that destruction of proteins can render a person poised at the borderline between male and female patterns of development.
Researchers completed a molecular analysis of a toddler who developed as a female despite having a male genetic background, termed XY sex reversal.
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.
Previous research has shown that mutations in SRY can 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.
Moreover, 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.
To figure out why the child was female, 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.
Researchers discovered the mutation of the back surface of SRY increased ubiquitin tagging and so accelerated destruction by the proteasome.
Regulation of male development 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 is responsible for rendering a genetic switch ambiguous in a human embryo (or any other animal).
Researchers suggest hat this case report was remarkable for both the family details and the molecular aspects.
How the child developed in the womb represented a race between proteasome destruction and DNA-based gene regulation.
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.
The study is supported by a contribution from the Cleveland Center for Membrane and Structural Biology, and in part by National Institutes of Health.
Citation: Racca JD, et al. (2016). Human Sex Determination at the Edge of Ambiguity Inherited XY Sex Reversal Due to Enhanced Ubiquitination and Proteasomal Degradation of a Master Transcription Factor. Journal of Biological Chemistry, published online. DOI: 10.1074/jbc.M116.741959.
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