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R-spondin1 is essential in sex determination, skin differentiation and malignancy


R-spondins are a recently characterized small family of growth factors. Here we show that human R-spondin1 (RSPO1) is the gene disrupted in a recessive syndrome characterized by XX sex reversal, palmoplantar hyperkeratosis and predisposition to squamous cell carcinoma of the skin. Our data show, for the first time, that disruption of a single gene can lead to complete female-to-male sex reversal in the absence of the testis-determining gene, SRY.

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Figure 1: Genetic analysis.
Figure 2: Mutation analysis and transcript analysis.
Figure 3: Pattern of expression of Rspo1.
Figure 4: Expression of Rspo1 in mouse XX and XY gonads, as shown by real-time PCR.
Figure 5: Phenotype of cultured keratinocytes.

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We are indebted to patients and clinicians for active collaboration in the research and with S. Bondanza and S. Pezzaia for technical help. We also thank M. Magliano for help in the in situ experiments. This work was supported by grants from Coperativa Est Ticino, Telethon, the European Community, the Ministero Italiano dell'Università e della Ricerca and the Consiglio Nazionale Delle Ricerche.

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Correspondence to Giovanna Camerino.

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Supplementary information

Supplementary Fig. 1

Haplotype analysis in patients and genome-wide SNP analysis. (PDF 21 kb)

Supplementary Fig. 2

Hypothetical RSPO1 proteins produced in patients. (PDF 40 kb)

Supplementary Fig. 3

Real-time PCR analysis on staged embryos. (PDF 90 kb)

Supplementary Table 1

Oligonucleotide sequences. (PDF 10 kb)

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Parma, P., Radi, O., Vidal, V. et al. R-spondin1 is essential in sex determination, skin differentiation and malignancy. Nat Genet 38, 1304–1309 (2006).

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