Mutations in MAP3K1 cause 46,XY disorders of sex development and implicate a common signal transduction pathway in human testis determination.
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.
New York University School of Medicine, New York, 10016, USA.
Alexander
A
Pearlman
Johnny
J
Loke
Cedric
C
Le Caignec
Stefan
S
White
Lisa
L
Chin
Andrew
A
Friedman
Nicholas
N
Warr
John
J
Willan
David
D
Brauer
Charles
C
Farmer
Eric
E
Brooks
Carole
C
Oddoux
Bridget
B
Riley
Shahin
S
Shajahan
Giovanna
G
Camerino
Tessa
T
Homfray
Andrew H
AH
Crosby
Jenny
J
Couper
Albert
A
David
Andy
A
Greenfield
Andrew
A
Sinclair
Harry
H
Ostrer
D000595:Amino Acid Sequence; D000818:Animals; D058490:Disorder of Sex Development, 46,XY / Q000235:genetics*; D005260:Female; D006801:Humans; D048728:MAP Kinase Kinase Kinase 1 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008297:Male; D009154:Mutation; D010375:Pedigree; D010766:Phosphorylation; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D013737:Testis / Q000196:embryology*
D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human