Mutations in MAP3K1 that cause 46,XY disorders of sex development disrupt distinct structural domains in the protein

Adam Chamberlin, Robert Huether, Aline Z. Machado, Michael Groden, Hsiao Mei Liu, Kinnari Upadhyay, O. Vivian, Nathalia L. Gomes, Antonio M. Lerario, Mirian Y. Nishi, Elaine M.F. Costa, Berenice Mendonca, Sorahia Domenice, Jacqueline Velasco, Johnny Loke, Harry Ostrer

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


Missense mutations in the gene, MAP3K1, are a common cause of 46,XY gonadal dysgenesis, accounting for 15-20% of cases [Ostrer, 2014, Disorders of sex development (DSDs): an update. J. Clin. Endocrinol. Metab., 99, 1503-1509]. Functional studies demonstrated that all of these mutations cause a protein gain-of-function that alters co-factor binding and increases phosphorylation of the downstream MAP kinase pathway targets, MAPK11, MAP3K and MAPK1. This dysregulation of the MAP kinase pathway results in increased CTNNB1, increased expression of WNT4 and FOXL2 and decreased expression of SRY and SOX9. Unique and recurrent pathogenic mutations cluster in three semi-contiguous domains outside the kinase region of the protein, a newly identified N-terminal domain that shares homology with the Guanine Exchange Factor (residues Met164 to Glu231), a Plant HomeoDomain (residues Met442 to Trp495) and an ARMadillo repeat domain (residues Met566 to Glu862). Despite the presence of the mutation clusters and clinical data, there exists a dearth of mechanistic insights behind the development imbalance. In this paper, we use structural modeling and functional data of these mutations to understand alterations of the MAP3K1 protein and the effects on protein folding, binding and downstream target phosphorylation. We show that these mutations have differential effects on protein binding depending on the domains in which they occur. These mutations increase the binding of the RHOA, MAP3K4 and FRAT1 proteins and generally decrease the binding of RAC1. Thus, pathologies in MAP3K1 disrupt the balance between the pro-kinase activities of the RHOA and MAP3K4 binding partners and the inhibitory activity of RAC1.

Original languageEnglish (US)
Article numberddz002
Pages (from-to)1620-1628
Number of pages9
JournalHuman molecular genetics
Issue number10
StatePublished - May 15 2019

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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