Mutations in <i>NR5A1</i> associated with 46,XY DSD.

<p>(A). Distribution of <i>NR5A1</i> mutations in relation to the functional domains of the protein. The DNA-binding domain (DBD) containing two zinc-finger motifs is indicated. The FtzF1 box stabilizes protein binding to DNA. The hinge region is important for stabilizing the ligand-binding domain and interacts with other proteins that control NR5A1 transcriptional activity. The AF2 domain recruits cofactors necessary for NR5A1 transactivating activity. (B) The sequence alignment of the distal portion of the hinge and the ligand-binding domain (LBD) of human NR5A1 protein as compared with those of other mammals. 1 to 10 of the predicted alpha helixes in the ligand-binding domain of NR5A1 are indicated as solid boxes, and corresponding amino acids in bold text. The position of the p.Trp279Arg and p.Arg313Cys are highlighted. The mutations fall either in the highly conserved Helix 3 (p.Trp279Arg) or in Helix 5 (p.Arg313Cys) of the ligand-binding domain. The mutation c.390delG was described previously <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0024117#pone.0024117-Loureno1" target="_blank">[20]</a>. (C) Evolutionary conservation of DNA binding domain of NR5A1. Sequence alignment of the evolutionary conserved DNA-binding domain of NR5A1 showing the position of the two zinc finger domains and the p.Arg39Pro mutation.