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

Alexander Pearlman, Johnny C. 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 journalArticle

92 Citations (Scopus)

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

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XY Disorders of Sex Development 46
Testis
Signal Transduction
Mutation
sry Genes
Gonadal Dysgenesis
RNA Splicing
Disorders of Sex Development
Chromosomes, Human, Pair 5
Gonads
Phosphorylation
Phenotype
Genes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Mutations in MAP3K1 cause 46,XY disorders of sex development and implicate a common signal transduction pathway in human testis determination. / Pearlman, Alexander; Loke, Johnny C.; Le Caignec, Cedric; White, Stefan; Chin, Lisa; Friedman, Andrew; Warr, Nicholas; Willan, John; Brauer, David; Farmer, Charles; Brooks, Eric; Oddoux, Carole; Riley, Bridget; Shajahan, Shahin; Camerino, Giovanna; Homfray, Tessa; Crosby, Andrew H.; Couper, Jenny; David, Albert; Greenfield, Andy; Sinclair, Andrew; Ostrer, Harry.

In: American Journal of Human Genetics, Vol. 87, No. 6, 10.12.2010, p. 898-904.

Research output: Contribution to journalArticle

Pearlman, A, Loke, JC, 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 & Ostrer, H 2010, 'Mutations in MAP3K1 cause 46,XY disorders of sex development and implicate a common signal transduction pathway in human testis determination', American Journal of Human Genetics, vol. 87, no. 6, pp. 898-904. https://doi.org/10.1016/j.ajhg.2010.11.003
Pearlman, Alexander ; Loke, Johnny C. ; Le Caignec, Cedric ; White, Stefan ; Chin, Lisa ; Friedman, Andrew ; Warr, Nicholas ; Willan, John ; Brauer, David ; Farmer, Charles ; Brooks, Eric ; Oddoux, Carole ; Riley, Bridget ; Shajahan, Shahin ; Camerino, Giovanna ; Homfray, Tessa ; Crosby, Andrew H. ; Couper, Jenny ; David, Albert ; Greenfield, Andy ; Sinclair, Andrew ; Ostrer, Harry. / Mutations in MAP3K1 cause 46,XY disorders of sex development and implicate a common signal transduction pathway in human testis determination. In: American Journal of Human Genetics. 2010 ; Vol. 87, No. 6. pp. 898-904.
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AU - Pearlman, Alexander

AU - Loke, Johnny C.

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

PY - 2010/12/10

Y1 - 2010/12/10

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