2 NOVEL SRY MISSENSE MUTATIONS REDUCING DNA-BINDING IDENTIFIED IN XY FEMALES AND THEIR MOSAIC FATHERS

Two novel mutations in the sex-determining gene SRY were identified by screening DNA from 30 sex-reversed XY females by using the SSCP assay . Both point mutations lead to an amino acid substitution in the DNA-b inding high-mobility-group domain of the SRY protein. The first mutati on, changing a serine at position 91 to glycine, was found in a sporad ic case. The second mutation, leading to replacement of a highly conse rved proline at position 125 with leucine, is shared by three members of the same family, two sisters and a half sister having the same fath er. The mutant SRY proteins showed reduced DNA-binding ability in a ge l-shift assay. Analysis of lymphocyte DNA from the respective fathers revealed that they carry both the wild-type and the mutant version of the SRY gene. The fact that both fathers transmitted the mutant SRY co py to their offspring implies that they are mosaic for the SRY gene in testis as well as in blood, as a result of a mutation during early em bryonic development.