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In-frame missense and splicing mutations (resulting in a 2 amino acid insertion or a 34 amino acid deletion) dispersed through the  MAP3K1  gene tilt the balance from the male to female sex-determining pathway, resulting in 46,XY disorder of sex development. These  MAP3K1  mutations mediate this balance by enhancing WNT/β-catenin/FOXL2 expression and β-catenin activity and by reducing SOX9/FGF9/FGFR2/SRY expression. These effects are mediated at multiple levels involving  MAP3K1  interaction with protein co-factors and phosphorylation of downstream targets. In transformed B-lymphoblastoid cell lines and NT2/D1 cells transfected with wild-type or mutant  MAP3K1  cDNAs under control of the constitutive CMV promoter, these mutations increased binding of RHOA, MAP3K4, FRAT1 and AXIN1 and increased phosphorylation of p38 and ERK1/2. Overexpressing RHOA or reducing expression of MAP3K4 in NT2/D1 cells produced phenocopies of the  MAP3K1  mutations. Using siRNA knockdown of RHOA or overexpressing MAP3K4 in NT2/D1 cells produced anti-phenocopies. Interestingly, the effects of the  MAP3K1  mutations were rescued by co-transfection with wild-type  MAP3K4 . Although  MAP3K1  is not usually required for testis determination, mutations in this gene can disrupt normal development through the gains of function demonstrated in this study.

Mutations in MAP3K1 tilt the balance from SOX9/FGF9 to WNT/β-catenin signaling