MAP3K7, a candidate gene for syndromic 46,XY DSD

Uyen Le Thanh Nha; Fard Shirin Moradi; Reyes Alejandra P; Thu Ha Nguyen; Thi Bich Ngoc Can; Gomes Adriana Tavares; Chi Dung Vu; Vincent R Harley

doi:10.1530/endoabs.118.PO48

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Endocrine Abstracts (2026) 118 PO48 | DOI: 10.1530/endoabs.118.PO48

IDSD2026 Poster Abstracts Poster Abstracts (93 abstracts)

MAP3K7, a candidate gene for syndromic 46,XY DSD

Thanh Nha Uyen Le ¹ , Shirin Moradi Fard ¹ , Alejandra P Reyes ² , Ha Nguyen Thu ³ , Ngoc Can Thi Bich ^3, , Adriana Tavares Gomes ⁴ , Dung Vu Chi ³ & Vincent R Harley ¹

Author affiliations

¹Centre for Endocrinology and Reproductive Health, Hudson Institute of Medical Research, Melbourne, Australia; ²Genetics Department, Children’s Hospital of Mexico Federico Gómez, Mexico City, Mexico; ³Vietnam National Children Hospital, Hanoi, Vietnam; ⁴Department of Pediatrics and Rady Children’s Hospital San Diego, University of California, San Diego, La Jolla, California, USA. Correspondence to: [email protected]

Background: MAP3K7 mutations cause Cardiospondylocarpofacial (CSCF) and Frontometaphyseal dysplasia 2 (FMD2), characterized by skeletal malformation, facial dysmorphism, cardiac abnormalities, hearing loss, and intellectual disability. However, involvement of MAP3K7 in gonadal development and DSD was not known.

Methods: Clinical informatiom of cases were gathered. Extracted DNA for whole exome sequencing analysis. MAP3K7 knock out was done by using CRIPSR technique. MAP3K7 mutagenesis to generate constructs carrying WT or MAP3K7 variants. TOP/FLOPFLASH assay on HEK293T cells overexpressing MAP3K7 WT or variants to examine the beta catenin signalling pathway. Western blot was used to determine p-p38 expression.

Results: We report three new syndromic cases of 46,XY DSD with cardiospondylocarpofacial (CSCF) or frontometaphyseal dysplasia type 2 (FMD2) carrying novel missense variants in MAP3K7. The DSD phenotypes include cryptorchidism and micropenis (Case #1 and #2), small testis (Case# 2) and hypospadias (in all three Cases). MAP3K7 is highly expressed in human fetal Sertoli cells (https://www.reproductivecellatlas.org/gonads/human-main-male/). MAP3K7 knock-out in NT2/D1 cells was lethal. MAP3K7 knock-out in HEK293T cells led to downregulation of GATA4 and FOG2 expression by RNA-Seq. All 3 MAP3K7 variants occur in the kinase domain at highly conservative positions among mammals. Like MAP3K1, MAP3K7 phosphorylated p38 - unexpectedly all 3 MAP3K7 variants over-phosphorylated p38 compared to wildtype. In TOPFLASH assays two MAP3K7 missense mutants (Case #1 & #2) ectopically activate beta catenin/Wnt signalling. Our data suggest that MAP3K7 contributes to male sex differentiation through its kinase activity and by regulating GATA4 and FOG2 expression, and antagonizing 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.

Conclusions: Our data suggests that MAP3K7 contributes to male sex differentiation through its kinase activity, regulating GATA4 and FOG2 expression, and antagonizing beta-catenin signalling