GENETIC CONTROL OF HUMAN GONADAL DIFFERENTIATION

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The essential role of the Y chromosome in primary male sex determination is well established and the gene that triggers this process is termed the testis-determining factor (TDF). Studies of the TDF locus in man have been facilitated by the existence of two conditions, 46,XY complete gonadal dysgenesis (lack of testis differentiation in subjects with a male karyotype), and 46,XX maleness (development of testes in subjects with an apparently female karyotype). The TDF locus has been mapped to the distal region of the short arm of the Y chromosome. A candidate gene for TDF has been cloned from this locus by Goodfellow and co-workers, and has been called sex-determining region Y (SRY). Several lines of evidence indicate that SRY is indeed the TDF. The SRY gene is a member of a family of DNA binding proteins, termed the high mobility group (HMG). Recent studies show that HMG proteins may influence gene transcription by binding to sequence specific sites and by changing the conformation of DNA. Hence, it is likely that SRY triggers testis determination by binding to sequence specific DNA sites. However, the physiologic binding site(s) of SRY in the human genome and the mode of action of SRY are unknown. Our principal hypothesis is that the SRY gene product controls male sex determination by initiating activation of a cascade of genes. The specific aims of this proposal are: 1) To identify specific SRY binding sites in the human genome; 2) to determine the influence of SRY on the conformation of DNA and on transcriptional activation; 3) To determine the influence of naturally occurring mutations in the SRY gene on the ability of SRY protein to interact with its specific binding sites. 4) To investigate further the genetic basis of 46,XY gonadal dysgenesis in additional subjects by investigating SRY mutations in affected individuals and by performing linkage analysis in kindreds with inherited forms of gonadal dysgenesis. These studies will provide new information and be the foundation for future studies to examine the complex interplay of the genes that are necessary for normal testis determination. They will also permit a better understanding of abnormal sex differentiation.