Genetic basis of XX males discovered

Italian team implicates R-spondin1 as an ovary-promoting sex-determination gene

By | October 16, 2006

A team of Italian researchers has identified a new sex-determination gene, according to a report in Nature Genetics. Genetic analysis has implicated R-spondin1, a member of a relatively new class of mitogens, as an ovary-promoting factor, the loss of which leads to complete sex reversal - that is, to XX males. Despite the notion that female sexual development is a "default" condition, researchers have long known there must be ovary-promoting factors. However, all previous candidates have come up short because they exhibited functional redundancy, according to Robin Lovell-Badge, of the Division of Medical Genetics at MRC National Institute for Medical Research in London. The new study is "a very important piece of work," Lovell-Badge told The Scientist. "I think it will stimulate a lot of activity." Giovanna Camerino, of the University of Pavia in Italy, and colleagues used genetic analysis of a consanguineous Italian family with four XX male brothers to map the gene to a 15-megabase region of chromosome 1. Sequencing of the 190 genes in that region identified a single base insertion in the gene for R-spondin1 (RSPO1); an unrelated individual with the same phenotype was found to have a deletion in the same region. (All five affected XX males also exhibit palmoplantar hyperkeratosis, and three are predisposed to squamous cell carcinoma of the skin.) "It's a beautiful piece of genetic detective work," Lovell-Badge said. During gonad development, both male and female embryos display low-level expression of the testis-promoting transcription factor Sox9. In a normal male, the Y chromosome gene, Sry, activates expression of Sox9, causing the protein to accumulate and stimulate development of Sertoli cells and, ultimately, of male sexual organs. In females, Sox9 is turned off, leading to the development of ovaries. XX sex-reversed individuals most typically arise when Sry is transferred to the X chromosome; XX males lacking SRY are "exceptionally rare," the authors write. "There has to be some mechanism for turning off Sox9 in the developing ovary, and we would guess - and this is what we don't know yet - that somehow R-spondin1 is involved in that process," Lovell-Badge explained. Camerino's expression analysis of RSPO1 in the mouse seemingly supports that hypothesis: RSPO1 expression rises in the developing female gonads at day E12.5, at the same time that Sox9 expression is rising in the developing male. "I thought the expression analysis in the mouse was a little weak," Lovell-Badge said. "I'd like to see more, but I'm sure that will come in time." R-spondin1 is one of four members of a new class of epithelial mitogens called the R-spondins. RSPO family members are protein ligands, which, like Wnt proteins, appear to act through receptor binding-induced stabilization of the transcription factor beta-catenin. Wnt4 is known to be active in developing female gonads, the authors noted, so "it is tempting to speculate that RSPO1 may synergize with Wnt4 in XX gonads to stabilize beta-catenin." This finding "comes in somewhat from left field," according to Walter Funk, vice president for research at Nuvulo, who co-authored a 2006 review of the R-spondin protein family. Previous work on RSPO1 indicated that it is widely expressed throughout the developing animal, so it would not have been surprising to find that individuals who lack the protein exhibit developmental defects in those tissues. However, "the fact that it results in actual sex reversal is unanticipated," Funk said. "I don't think most people would have put money on this one." Teasing out how RSPO1 synergizes with or competes against Sox9, Wnt4, and other sex-development genes will only come from mouse studies, Lovell-Badge said. "It will be interesting to find out what happens when RSPO1 is mutated in mice. With these other genes that have been put forward as ovary-promoting candidates [like Wnt4], the mouse mutations have been disappointing to some extent." Also needed, Funk said, are studies to probe the developmental roles of the other R-spondins. "To date, no one has shown a difference in the biochemistry of these four proteins -- all four R-spondin members induce beta-catenin to the same degree. But nature didn't invent four of these proteins for massive redundancy. They will all have unique functions." Jeffrey M. Perkel Links within this article: P. Parma et al., "R-spondin1 is essential in sex determination, skin differentiation, and malignancy," Nature Genetics, advance online publication, Oct. 15, 2006 Robin Lovell-Badge University of Pavia Walter Funk K.A. Kim et al., "R-Spondin proteins: a novel link to beta-catenin activation," Cell Cycle, 5:23-6, 2006.

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