We study the genetic basis of rare genetic disorders, notably disorders found in isolated populations and disorders of sex development, to identify not only the mutational basis, but also the molecular mechanisms.
Currently, we are investigating the roles of members of the MAP kinase pathway in normal testicular development - effects on gene expression, protein phosphorylation, interaction with co-factors, cellular phenotypes. We are also using whole genome sequencing to identify the genetic basis of disorders of gonadal development and other rare disorders.
Bogani D, et al. Loss of mitogen-activated protein kinase kinase kinase 4 (MAP3K4) reveals a requirement for MAPK signalling in mouse sex determination. PLoS Biol. 2009 Sep;7(9):e1000196.
Pearlman A, et al. 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, 2010.
Warr N, et al. Minor abnormalities of testis development in mice lacking the gene encoding the MAPK signalling component, MAP3K1. PLoS One. 6(5):e19572, 2011.
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, Sinclair A, Ostrer H. 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, 2010.
Loke J, Ostrer H. Rapidly screening variants of uncertain significance in the MAP3K1 gene for phenotypic effects. Clin Genet. 81:272-7, 2012