In 5 patients from 4 unrelated families with 46,XX sex reversal (SRXX4; 617480), Bashamboo et al. (2016) identified a c.274C-T transition in the NR5A1 gene that resulted in an arg-to-trp substitution at codon 92 (R92W). In 1 of these families, a sister had 46,XY sex reversal (SRXY3; 612965) due to the same variant. In 2 families, the variant was maternally inherited, in 1 it occurred as a de novo event, and in 1 family the mutation was not present in the father, but the mother was deceased and no DNA was available. The variant was absent from the dbSNP (build 138), ExAC, and 1000 Genomes Project databases, and from an internal database containing exomes of 400 individuals as well as more than 1,000 fertile controls Sanger sequenced for NR5A1. The arg92 residue in NR5A1 is evolutionarily conserved to zebrafish.
In 3 unrelated probands with 46,XX (ovo)testicular disorder of sexual development (DSD), Baetens et al. (2017) found a c.274C-T transition in exon 4 of the NR5A1 gene (c.274C-T, NM_004959.4) that resulted in an R92W substitution in the protein. Several unaffected female first-degree relatives of the probands from each of the families also carried this mutation, suggesting that this variant is weakly penetrant. A potential founder effect was suggested by haplotype analysis. The arg92 residue is highly evolutionarily conserved to zebrafish and located in the Ftz-F1 region, probably involved with DNA-binding specificity and stability. The R92W mutation was absent from the Exome Sequencing Project (ESP), ExAC, Genome of the Netherlands (GoNL), and 1000 Genomes Project databases and from an in-house exome database.
Igarashi et al. (2017) identified the R92W mutation (c.274C-T, NM_004959.4) in 2 unrelated Japanese patients with 46,XX testicular/ovotesticular DSD. The mutation was absent from the clinically normal mothers and from 200 Japanese controls. One of the fathers, who was unaffected, carried the mutation; the other father was not available for analysis. In vitro assays showed that the mutant protein was less sensitive than wildtype to NR0B1 (300473)-induced suppression on the SOX9 (608160) enhancer element.
