Mutations in MAP3K1 cause 46,XY disorders of sex development and implicate a common signal transduction pathway in human testis determination

Alexander Pearlman, Johnny Loke, Cedric Le Caignec, Stefan White, Lisa Chin, Andrew Friedman, Nicholas Warr, John Willan, David Brauer, Charles Farmer, Eric Brooks, Carole Oddoux, Bridget Riley, Shahin Shajahan, Giovanna Camerino, Tessa Homfray, Andrew H. Crosby, Jenny Couper, Albert David, Andy GreenfieldAndrew Sinclair, Harry Ostrer

Research output: Contribution to journalArticlepeer-review

142 Scopus citations

Abstract

Investigations of humans with disorders of sex development (DSDs) resulted in the discovery of many of the now-known mammalian sex-determining genes, including SRY, RSPO1, SOX9, NR5A1, WT1, NR0B1, and WNT4. Here, the locus for an autosomal sex-determining gene was mapped via linkage analysis in two families with 46,XY DSD to the long arm of chromosome 5 with a combined, multipoint parametric LOD score of 6.21. A splice-acceptor mutation (c.634-8T>A) in MAP3K1 segregated with the phenotype in the first family and disrupted RNA splicing. Mutations were demonstrated in the second family (p.Gly616Arg) and in two of 11 sporadic cases (p.Leu189Pro, p.Leu189Arg) - 18% prevalence in this cohort of sporadic cases. In cultured primary lymphoblastoid cells from family 1 and the two sporadic cases, these mutations altered the phosphorylation of the downstream targets, p38 and ERK1/2, and enhanced binding of RHOA to the MAP3K1 complex. Map3k1 within the syntenic region was expressed in the embryonic mouse gonad prior to, and after, sex determination. Thus, mutations in MAP3K1 that result in 46,XY DSD with partial or complete gonadal dysgenesis implicate this pathway in normal human sex determination.

Original languageEnglish (US)
Pages (from-to)898-904
Number of pages7
JournalAmerican Journal of Human Genetics
Volume87
Issue number6
DOIs
StatePublished - Dec 10 2010
Externally publishedYes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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