Garrett A. Duncan, Ph.D,
"a terrific asset as a teacher and colleague"
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Garrett A. Duncan, Ph.D, "a terrific asset as a teacher and colleague" |
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Rare bone disorder links gene deletion in two Navajo patients By Gila Z. Reckess Two seemingly unrelated Native Americans have one painful thing in common: juvenile Paget's disease (JPD), an extremely rare bone metabolism disorder. Researchers in the School of Medicine and Shriners Hospitals for Children have discovered that these two patients also share a unique genetic defect. The research team found that both patients are completely missing the gene for a recently discovered protein called osteoprotegerin, known to protect bone. The study, which appeared in a recent issue of The New England Journal of Medicine, is the first to identify a genetic cause for JPD.
JPD has been reported only in about 40 people worldwide. The painful skeletal disease is characterized by abnormally fast formation and breakdown of bone throughout the body, resulting in debilitating fractures and deformities beginning soon after birth. These features are similar to the much more common adult disease called Paget's disease of bone, the second most prevalent metabolic bone disorder after osteoporosis. But JPD appears to affect all bones in the body, whereas Paget's disease of bone involves only a select few. The research team examined DNA samples from two Native Americans. The first was referred to St. Louis from New Mexico in 1996 for confirmation of diagnosis and treatment at 1 year of age. The team later learned that a second JPD patient, described in medical literature in 1979, also was living in New Mexico. The second patient contacted the investigators and voluntarily sent her blood samples for genetic study. The researchers tested the patients' blood for a gene that makes osteoprotegerin, a protein discovered only a few years ago. Recent studies have found that mice lacking the protein have a condition in which bone formation and breakdown is rapid, seemingly similar to osteoporosis. The results were surprising. Neither patient had any trace of the gene for osteoprotegerin. "At first we thought there must be something wrong with our DNA studies," said Steven Mumm, Ph.D., research assistant professor of medicine and one of the lead investigators of the study. "Instead, we realized this was a major finding." Genetic analysis of healthy individuals confirmed the expected presence of two copies of the gene for osteoprotegerin. However, analysis of the JPD patients' healthy parents revealed that each had only one copy of the gene. Furthermore, no osteoprotegerin was found in the blood of the two patients with JPD. The researchers conclude that these results provide both a cause and a mechanism for this rare bone disease, at least for these two Native Americans. Thanks to simultaneous advances in the Human Genome Project, centered in part at the University, the team was able to pinpoint exactly where DNA had broken off in these two patients. The results were startling: The genetic damage was identical in both patients. The researchers concluded that these two patients likely share a common ancestor, perhaps dating back a century or more. "In a way, this also is a sociology story," Whyte said. "Our findings appear to represent the emergence of a 'founder effect' in this population that underwent a 'bottleneck' constriction years ago. "The Navajo Nation de-creased from perhaps several hundred thousand individuals to about 6,000 in the 1860s. As the population then regrew, the missing gene apparently was passed on to their offspring. Eventually, people with only one copy of the osteoprotegerin gene married and had children with no copies of the gene." The team now is evaluating other patients worldwide with varying forms of JPD, who so far do not appear to have any defects in the osteoprotegerin gene. According to Whyte, this research will not only enable prenatal diagnosis for JPD in the Navajo population, but also suggests that osteoprotegerin may be a potential treatment for affected individuals. They also expect their findings to help elucidate the role of osteoprotegerin and other key proteins in bone formation and breakdown, shedding light on Paget's disease of bone, osteoporosis and other common metabolic bone disorders. |
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