What does this research mean for the field?

A single-nucleotide insertion in the Sox9 enhancer, Enh13, disrupts transcriptional repression by pro-female factors, leading to inappropriate Sox9 upregulation and complete XX female-to-male sex reversal. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

To understand how mutations in the Enh13 enhancer can alter sex determination from XX to male.

April 11, 2026Nature Communications1 citationsOpen Access

A single-nucleotide enhancer mutation overrides chromosomal sex to drive XX male development

EAElisheva AbberbockBar-Ilan University MRMeshi RidnikBar-Ilan University ISIsabelle StévantCentre National de la Recherche Scientifique

Key Points

To understand how mutations in the Enh13 enhancer can alter sex determination from XX to male.
Performed genetic analysis to identify mutations in Enh13.
Assessed the role of Enh13 in regulating Sox9 expression.
Investigated the effects of pro-female factors on Enh13's activity.
Identified a single-nucleotide mutation in Enh13 responsible for XX male development.
Demonstrated that Enh13 mutations lead to inappropriate upregulation of Sox9 in the absence of Sry.
Showed that pro-female factors repress Enh13, impacting sex determination.

Abstract

Mammalian sex determination is governed by two mutually antagonistic genetic programs that must be precisely balanced. Activation of Sox9 initiates testis development, while its repression is essential for ovarian fate. The distal enhancer, Enh13, is essential for testicular Sox9 expression, with its deletion or inactivation resulting in complete XY sex reversal. Here, we show that subtle mutations within Enh13, including a single-nucleotide insertion, produce the reciprocal phenotype: complete XX female-to-male sex reversal. Pro-female factors can strongly repress Enh13, suggesting they mediate Sox9 silencing in ovaries. The small enhancer alterations facilitate inappropriate Sox9 upregulation in the absence of Sry, triggering the testicular transcriptome and repressing ovarian gene expression. Mechanistically, these mutations disrupt the repressive effect of RUNX1, NR5A1 and GATA4, thereby reprogramming enhancer activity. Our findings identify Enh13 as a central regulatory hub, integrating opposing sex-specific cues, hence acting as a binary switch for gonadal fate. A single base pair insertion in the Sox9 enhancer, Enh13, mediates XX female-to-male sex reversal. This subtle non-coding mutation reconfigures transcriptional regulation, enhances Sox9 expression, revealing Enh13 as a binary switch governing sexual fate.

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