Study by genetics researchers sheds light on genital birth defects

One of the most common birth defects in boys occurs when the urethra develops incompletely, affecting where the opening develops on the penis. Now, researchers from the University of Florida Genetics Institute have discovered clues as to what may cause this common defect — information that could shed light on other birth defects as well.

Hypospadias occurs when the urethra develops incompletely. Instead of opening at the tip of the penis, the hole appears further up the shaft.

Marissa Gredler, Ph.D., a graduate student working in the lab of UFGI faculty member Martin Cohn, Ph.D., said scientists still don’t know as much as they would like about the processes of normal embryonic development. Gaining more understanding about these processes is crucial, because unrelated studies in recent years have revealed an uptick in the number of baby boys born with genital malformations, she said. A 1997 study by the Centers for Disease Control and Prevention showed that between 1970 and 1993, rates of genital malformations increased twofold, according to a national birth defects surveillance system based on hospital discharge data.

In a study published in the June issue of the journal Development, Gredler studied mice to examine how a gene that codes for the protein fibroblast growth factor receptor 2, or Fgfr2, regulates urethral tube development. This protein influences cell division and cell adhesion, and, therefore, tissue development. Gredler collaborated with Cohn and researcher Ashley Seifert, Ph.D., a professor at the University of Kentucky.

Previous studies by other scientists revealed that removing Fgfr2 function from the tissues where it exists disrupted external genital development, Gredler said. However, researchers could not pinpoint which of these tissues were specifically related to urethral development, or what Fgfr2 was doing in the cells of those tissues, Gredler said.

The UFGI researchers used different mouse lines to test the hypothesis that one tissue where Fgfr2 is expressed might play a greater role in driving urethral development than another region. Gredler found that deleting Fgfr2 from only the embryonic skin, or only in the urethra, led to different urethral defects.

The urethra develops as a tube. Sometimes it develops abnormally because of a genetic mutation passed on by a parent. However, it can also develop abnormally because of exposure to a chemical introduced from the exterior that might affect hormone signaling, such as those found in certain medications or other environmental factors.

One hypothesis is that some malformations are caused when gene expression is influenced by endocrine disrupting-compounds, Gredler said.

Gredler’s research is important for understanding the causes of genital malformations in humans — a fairly common birth defect. It also lends itself to increased understanding for malformations of other organs that develop as tubes, such as the heart and brain.

“I think that understanding the development of dimorphic structures is very interesting and exciting,” Gredler said. “How tubes develop is a fascinating process that we know little about.”