ESPE Yearbook of Paediatric Endocrinology

Front Genet. 2022 Mar 3;13:736988. PMID: 35309143, doi: 10.3389/fgene.2022.736988.

Brief Summary: This molecular study highlights a novel mechanism of action of Mitogen-activated protein kinase kinase kinase 1 (MAP3K1) in the development of testicular dysgenesis.

MAP3K1 is one of the most common genes that has been identified to cause 46, XY DSD and variants are attributed to ~14-18% of the 46,XY DSD cases (1,2). It can present as complete or partial gonadal dysgenesis even within the same kindred, with clinical manifestations ranging from severe DSD to milder phenotypes such as hypospadias, cryptorchidism, and micropenis.

Functional studies of MAP3K1 variants have demonstrated a gain of function effect, causing increased phosphorylation of downstream targets resulting in decreased expression of SOX9, important for the development of the testis, and increased expression of β-catenin. These gene expression changes mimic the signaling pathway in ovarian development and thus result in abnormal testicular development.

These authors tested the pro-ovarian Wnt4/β-catenin/FOXL2 signalling pathway in two affected siblings with 46,XY DSD due to a novel missense c.556A > G/p.R186G variant in the MAP3K1 gene. The healthy 46,XX mother carried the same variant. These patients had normal female external genitalia and complete gonadal dysgenesis. One of the sisters had bilateral dysgerminoma. The authors have transiently transfected testicular teratoma cells (NT2/D1) and ovary-derived granulosa cells (KGN) with wild-type and MAP3K1^R186G variants and showed reduced binding of the MAP3K1^R186G variant to Ub. The lower ubiquitination level of MAP3K1^R186G caused increased stability and increased expression of MAP3K1^R186G protein. They have also shown higher expression and activity of p38 and GSK3β which subsequently led to overactivity of the Wnt4/β-catenin pathway. FOXL2 mRNA and protein expression in the mutant group was increased and DMRT1 and FGFR2 expression were decreased compared to the wild-type group.

Overall, this study increases our understanding of the mechanism of action of MAP3K1 showing that the MAP3K1^R186G variant upregulated in vitro expression of genes associated with ovarian development (including WNT4, β-catenin-CTNNB1, and FOXL2) and downregulated the expression of testicular development-related genes (FGFR2 and DMRT1).

References: 1. Eggers S, Sadedin S, van den Bergen JA, Robevska G, Ohnesorg T, Hewitt J, Lambeth L, Bouty A, Knarston IM, Tan TY, Cameron F, Werther G, Hutson J, O’Connell M, Grover SR, Heloury Y, Zacharin M, Bergman P, Kimber C, Brown J, Webb N, Hunter MF, Srinivasan S, Titmuss A, Verge CF, Mowat D, Smith G, Smith J, Ewans L, Shalhoub C, Crock P, Cowell C, Leong GM, Ono M, Lafferty AR, Huynh T, Visser U, Choong CS, McKenzie F, Pachter N, Thompson EM, Couper J, Baxendale A, Gecz J, Wheeler BJ, Jefferies C, MacKenzie K, Hofman P, Carter P, King RI, Krausz C, van Ravenswaaij-Arts CM, Looijenga L, Drop S, Riedl S, Cools M, Dawson A, Juniarto AZ, Khadilkar V, Khadilkar A, Bhatia V, Dũng VC, Atta I, Raza J, Thi Diem Chi N, Hao TK, Harley V, Koopman P, Warne G, Faradz S, Oshlack A, Ayers KL, Sinclair AH. Disorders of sex development: insights from targeted gene sequencing of a large international patient cohort. Genome Biol. 2016 Nov 29;17(1):243. doi: 10.1186/s13059-016-1105-y. PMID: 27899157; PMCID: PMC5126855.