TY - JOUR
T1 - Mutations in MAP3K1 cause 46,XY disorders of sex development and implicate a common signal transduction pathway in human testis determination
AU - Pearlman, Alexander
AU - Loke, Johnny
AU - Le Caignec, Cedric
AU - White, Stefan
AU - Chin, Lisa
AU - Friedman, Andrew
AU - Warr, Nicholas
AU - Willan, John
AU - Brauer, David
AU - Farmer, Charles
AU - Brooks, Eric
AU - Oddoux, Carole
AU - Riley, Bridget
AU - Shajahan, Shahin
AU - Camerino, Giovanna
AU - Homfray, Tessa
AU - Crosby, Andrew H.
AU - Couper, Jenny
AU - David, Albert
AU - Greenfield, Andy
AU - Sinclair, Andrew
AU - Ostrer, Harry
N1 - Funding Information:
This study was supported in part by the US National Institutes of Health, the Medical Research Council of the United Kingdom, and the National Health and Medical Research Council of Australia.
PY - 2010/12/10
Y1 - 2010/12/10
N2 - 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.
AB - 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.
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U2 - 10.1016/j.ajhg.2010.11.003
DO - 10.1016/j.ajhg.2010.11.003
M3 - Article
C2 - 21129722
AN - SCOPUS:78649781937
SN - 0002-9297
VL - 87
SP - 898
EP - 904
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 6
ER -