December 2, 2004
Complex genetics of collagen disorders
Dr. Peter Byers has spent most of his career working with children and adults affected by genetic collagen disorders, in which the body’s connective tissues (skin, bones, tendons, ligaments and blood vessels) don’t form properly, and with their families. Osteogenesis imperfecta, or brittle bone disease, is one of these disorders. It can have a range of effects, from bone and connective tissue so damaged that a newborn dies immediately, to bone damage so slight that it’s not visible, although the person may have a higher risk of breaking a bone. He also counsels families affected by these diseases and couples considering a pregnancy after a child has been born with a collagen disorder.
At the same time, he has been working in the laboratory, often with colleagues from other fields, to understand the genetic mistakes that produce these disorders. He is a UW professor of pathology and of medicine in the Division of Medical Genetics, and also has adjunct appointments in genome sciences and oral biology.
After a decade in which there has been what he calls “an explosion in human genetics,” most critically the sequencing of the human genome, he finds considerable hope in the increased understanding of how things go wrong, and yet believes that it will be some time before these genetic errors can be simply “fixed.”
“In the collagen genes we study,” Byers says, “we now understand just how very subtle these errors can be. Just a single change in one of 40,000 nucleotides within a gene can produce life-threatening effects. It just takes that one error.
“Organisms that have been evolving for millions of years are very fine-tuned in such a way that certain genetic errors can really cause a whole body system to be ‘bent out of shape.’ We have spent a lot of time and effort trying to understand why certain key changes in genes are simply not tolerable, while others don’t matter much or just produce normal human variations, like hair color or a strong jaw.”
While the genetic errors he studies can be inherited, many of them are considered spontaneous, because they just appear without warning. They can be introduced when genetic material is copied for cell division, or they can show up as a mutation that is only present in the single germ cells (sperm or egg) that will be fertilized.
Byers will speak on “Chaos out of Order: Splicing and Mosaicism in Genetic Collagen” at the next Science in Medicine Lecture at noon, Thursday, Dec. 9, in room T-625 of the Health Sciences Center. The lecture is open to everyone.
Byers and his colleagues have spent many years trying to understand why mutations in the same gene can have very different effects in people. Two ideas have been influential in their studies: the effects of splicing mutations, and the number of cells in the body that have mutations. In the collagen genes they are studying, there are 52 different “packages,” or exons, of information that tell the cells how to make a protein.
For the cell to use this information, the DNA of the gene is first made into an RNA copy and then the separate exons are spliced together by removing the intervening material, called introns. There are sequences at the ends of the introns that say “cut here and paste there,” Byers explains. Errors can show up at the splicing sites when the genes are copied, and these errors can lead to loss of information or duplication.
“These mutations account for about a third of the errors we see in some collagen genes,” Byers says, “but just from seeing the precise error we cannot always predict how the cells will process the RNA. Studying cells from people with these disorders has taught us a lot about this process, which is important in these and other genetic conditions.”
Mosaicism refers to the situation in which there are mutations in one copy of a gene within some cells in an organism, but not in other cells. If these mutations affect genes in the cells for eggs or sperm, they can cause problems for offspring even if the parents are clinically unaffected. The origin and frequency of mosaicism has been a central theme of Byers’ studies with his colleagues.
For patients and families with these disorders, the leaps in genetic information available have made a difference, but not yet produced a cure.
Byers firmly believes in the importance of being able to explain to families exactly what has happened when a child is born with a genetic disorder. “Knowledge really is power,” he says, “and it can be especially important for parents to understand that this did not happen because of something they did, or didn’t do.”
For couples who are contemplating a pregnancy and concerned about a certain mutation, physicians and genetic counselors are now able to offer a range of options, including in vitro fertilization and checking for the mutation at a very early stage before the embryo is implanted in the womb.
The increased ability of physicians and genetics clinics to provide a clear diagnosis and a name for a disorder has been important, too, Byers notes. Parent-child networks and peer groups that offer support and information have made a big difference in the resources and care available, especially for people who live in small towns or rural areas. Along with providing real assistance, these groups are working with physicians to understand the molecular picture. Byers is a member of medical advisory groups for the Osteogenesis Imperfecta Foundation, the Ehlers-Danlos National Foundation and the National Marfan Foundation.
“For now,” Byers says, “we can’t fix the gene involved, but we can offer many therapies for kids born with these disorders. We also understand much more about how these mutations occur and how to clearly identify them.”
Byers earned a bachelor’s degree from Reed College in Portland and his M.D. from Case Western Reserve University in Cleveland. After an internship and residency in internal medicine at the University of California Hospitals in San Francisco, he was a research associate in biochemistry at the National Institutes of Health in Bethesda, Md.
He came to the UW in 1974 as a senior fellow in biochemistry and medical genetics and joined the faculty as an assistant professor of pathology and medicine. He has been a full professor since 1986. He directs the Genetics Clinic at UW Medical Center and the Collagen Diagnostic Laboratory in the Department of Pathology, and sees patients as an attending physician at the clinic and as a consultant at Children’s.
