PMID:21129722

Citation	Pearlman, A, Loke, J, Le Caignec, C, White, S, Chin, L, Friedman, A, Warr, N, Willan, J, Brauer, D, Farmer, C, Brooks, E, Oddoux, C, Riley, B, Shajahan, S, Camerino, G, Homfray, T, Crosby, AH, Couper, J, David, A, Greenfield, A, Sinclair, A and Ostrer, H (2010) Mutations in MAP3K1 cause 46,XY disorders of sex development and implicate a common signal transduction pathway in human testis determination. Am. J. Hum. Genet. 87:898-904
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.
Links	PubMed PMC2997363 Online version:10.1016/j.ajhg.2010.11.003
Keywords	46, XY Disorders of Sex Development/genetics; Amino Acid Sequence; Animals; Female; Humans; MAP Kinase Kinase Kinase 1/chemistry; MAP Kinase Kinase Kinase 1/genetics; MAP Kinase Kinase Kinase 1/metabolism; Male; Mutation; Pedigree; Phosphorylation; Sequence Homology, Amino Acid; Signal Transduction; Testis/embryology
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:M3K1		GO:0004672 : protein kinase activity	ECO:0000314:		F		In figures 4A the effects MAP3K1 mutations on phosphorylation of downstream targets were examined by quantitative immunoblot analysis. Levels of phospho-ERK were increased in all the mutant cell lines in comparison to wild-type	complete CACAO 6394

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