MAP3K7 novel variants in syndromic 46,XY DSD

Mutations in MAP3K7 are responsible for two distinct syndromes Cardiospondylocarpofacial (CSCF) and Frontometaphyseal dysplasia 2 (FMD2). Both are characterized by skeletal malformations, facial dysmorphisms, hearing loss, and mild intellectual disability. While cardiac defects are predominant in CSCF, keloid scar is a distinct feature in FMD2. Problem with gonadal development and disorders of sexual development (DSD) have not been previously chracterized. Here we report three syndromic cases of 46,XY DSD with CSCF or FMD2, each carrying a novel heterozygous missense variants in MAP3K7 (NM_145331.3:c.250G>A; p.V84M, NM_145331.3:c.195A>G; p.I65M, and NM_145331.3: c.574A>G; p.S192G). The DSD phenotypes include cryptorchidism, micropenis, small testis, and hypospadias. In silico tools predict all three variants are deleterious. All three MAP3K7 variants occur in the kinase domain at highly conservative positions among mammals. MAP3K7 is highly expressed in human fetal Sertoli cells. MAP3K7 knock-out in HEK293T cells led to downregulation of GATA4 and FOG2 expression by RNA-Seq. Like MAP3K1, MAP3K7 phosphorylated p38 while all three MAP3K7 variants did not alter phosphorylated p38 compared to wildtype in HEK293TMAP3K7-/- cells. Two MAP3K7 missense mutants (p.V84M and p.I65M) ectopically activate ovarian beta catenin/ Wnt signalling in TOPFLASH assays. Our data suggest that MAP3K7 contributes to male sex differentiation by increasing expression of pro-testis genes GATA4 and FOG2 in HEK293TMAP3K7-/- cells and antagonizing pro-ovarian beta-catenin signalling, and that one or more of these activities were likely affected in 3 cases of 46,XY DSD with CSCF/FMD2 during sex development.