Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/63068
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Type: Journal article
Title: Mutations in MAP3K1 cause 46,XY disorders of sex development and implicate a common signal transduction pathway in human testis determination
Author: 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, A.
Couper, J.
David, A.
Greenfield, A.
et al.
Citation: American Journal of Human Genetics, 2010; 87(6):898-904
Publisher: Univ Chicago Press
Issue Date: 2010
ISSN: 0002-9297
1537-6605
Statement of
Responsibility: 
Alexander Pearlman... Jenny Couper... et al.
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.
Keywords: Testis
Animals
Humans
MAP Kinase Kinase Kinase 1
Pedigree
Signal Transduction
Amino Acid Sequence
Sequence Homology, Amino Acid
Phosphorylation
Mutation
Female
Male
Disorder of Sex Development, 46,XY
Rights: Copyright © 2010 The American Society of Human Genetics. Published by Elsevier Inc.
DOI: 10.1016/j.ajhg.2010.11.003
Appears in Collections:Aurora harvest
Paediatrics publications

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