GENETIC CONTROL OF HUMAN GONADAL DIFFERENTIATION

Project: Research project

Description

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.
StatusFinished
Effective start/end date6/1/9311/30/96

Funding

  • National Institutes of Health
  • National Institutes of Health: $171,988.00
  • National Institutes of Health

Fingerprint

Medical Genetics
sry Genes
Testis
Y Chromosome
Human Genome
Karyotype
Genes
Sex-Determining Region Y Protein
High Mobility Group Proteins
Gonadal Dysgenesis
Nucleic Acid Conformation
Mutation
Aptitude
DNA-Binding Proteins
Transcriptional Activation

ASJC

  • Medicine(all)