title: Mutations in MAP3K1 tilt the balance from SOX9/FGF9 to WNT/β-catenin signaling.
abstract: 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.
authors.affiliation: Department of Pathology and.
authors.forename: Johnny
authors.initials: J
authors.lastname: Loke
authors.forename: Alexander
authors.initials: A
authors.lastname: Pearlman
authors.forename: Orietta
authors.initials: O
authors.lastname: Radi
authors.forename: Orsetta
authors.initials: O
authors.lastname: Zuffardi
authors.forename: Ursula
authors.initials: U
authors.lastname: Giussani
authors.forename: Rosanna
authors.initials: R
authors.lastname: Pallotta
authors.forename: Giovanna
authors.initials: G
authors.lastname: Camerino
authors.forename: Harry
authors.initials: H
authors.lastname: Ostrer
mesh_terms: D001483:Base Sequence; D045744:Cell Line, Tumor; D004252:DNA Mutational Analysis; D005260:Female; D051525:Fibroblast Growth Factor 9 / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D048728:MAP Kinase Kinase Kinase 1 / Q000235:genetics* / Q000378:metabolism; D008297:Male; D020125:Mutation, Missense; D055758:SOX9 Transcription Factor / Q000378:metabolism*; D019849:Sex Determination Processes; D060449:Wnt Signaling Pathway
chemical_list: C496459:FGF9 protein, human; D051525:Fibroblast Growth Factor 9; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human