XX individuals with mutated RSPO1 gene develop:
XX humans homozygous for loss-of-function RSPO1 mutations present with complete female-to-male sex reversal clinically. Without Rspo1 amplification of Wnt4/β-catenin cascade, ovarian program collapses and Sox9 becomes derepressed, causing supporting cells to transdifferentiate into Sertoli-like cells organizing testis tubules and synthesizing androgens. Phenotype includes testes or ovotestes, masculinized external genitalia, palmoplantar hyperkeratosis and predisposition to squamous cell carcinoma. Mouse knockout mirrors masculinized gonads with ectopic Sox9, male vasculature and steroidogenes
Ref: Nature, RSPO1 mutations cause XX sex reversal; Gilbert Chapter 6: RSPO1 required for ovary.
