Kapur to speak on studies of embryonic gene expression

As 1999 ended, many of us were experiencing at least a twinge of apprehension. Would the Y2K bug bring our technological society to a crashing halt? Intuitively, we knew a mistake from the past was about to manifest itself in the present.

Raj Kapur Photo by Gavin Sisk

However, there were solutions. Systems operators identified the errors and developed coded solutions that kept our networks running smoothly as the clock ticked past midnight on Dec. 31, 1999.

Similarly, genetic scientists are hard at work identifying the built-in errors that bring us to a halt by crippling us with disease. Their efforts also include pinpointing the precise moments when errors will manifest themselves in our systems and developing solutions to fix them. One of the more advanced models for conducting such research concerns Hirschsprung disease and the mutations in seven known genes that cause it.

Dr. Raj Kapur, an associate professor of pathology, explains the disease is caused by an absence of neurons in the distal part of the large intestine. The absence of neurons prevents the large intestine from relaxing, which causes obstruction. Hirschsprung disease affects one in 5,000 people and is usually diagnosed shortly after birth. Doctors treat it by removing the diseased part of the intestine, but it can be life threatening and surgery is not an option in some cases.

Kapur will discuss his research on Hirschsprung disease in a Science in Medicine Lecture, titled “Manipulating Gene Expression in the Embryonic Gastrointestinal Neurons,” on Thursday, Jan. 20, from noon to 1 p.m. in room T-625 of the Health Sciences Center.

In the developing embryo, the cells that give rise to the neurons in the gut are located in the neural crest, a group of initially homologous cells that migrate to all different parts of the body. At specific points that researchers have begun to identify along the developmental path, genetic mutations cause the system to fail, and neurons destined to colonize the gut are prevented from progressing any further.

Kapur’s main approach to understanding this problem is to study transgenic mice. These mice are bred to carry spontaneous or genetically-engineered mutations that cause Hirschsprung disease. At the same time, they are also given a gene that researchers suspect may correct the mutation.

“In some cases, when the corrective gene is expressed at the right time, the underlying defect is suppressed and the disease can be prevented,” Kapur said. On a certain level, such results represent a treatment for Hirschsprung disease, but one far from clinical application. Before that step occurs scientists may have to solve the problem of “incomplete penetrance,” Kapur added.

Incomplete penetrance is the phrase used to describe why a given mutation in a given gene does not always result in disease. Researchers suspect one of two reasons for the phenomenon. Either there are other genes involved that suppress or promote the primary genetic mutation, or there are environmental factors, maternal exposures, for instance, that influence the migrating neurons in a way that allows the primary mutation to manifest as a birth defect.

Out of the seven genes with known mutations that cause Hirschsprung disease, five of the genes are expressed in the neural crest cells themselves, while the other two genes are expressed in adjacent cells during embryonic development. Not every individual with a mutation in one of these genes develops the disease. The severity of the disease also varies among individuals.

Curiously, Kapur said, there is a four to one predominance of Hirschsprung disease in males, which has prompted researchers to search for a gene on the X or Y chromosomes that may function as a modifier by helping express the primary mutation.

Until the problem of incomplete penetrance is solved, the treatment for the disease will remain post-natal surgical removal of the affected part of the intestine. Eventually, however, researchers hope to be able to develop a drug that women with a pregnancy at risk for the disease can take orally to suppress the genetic defect in the embryo.

Kapur, a perinatal pathologist at UW Medical Center, received a Ph.D. in anatomy and cell biology in 1986 and an M.D. in 1988 from the University of Southern California, Los Angeles. He completed a residency and fellowship at the UW and joined the faculty in 1991. ¶

Will Morton