Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Rare childhood bone disorder linked to gene deletion in two Navajo patients

18.07.2002

Two seemingly unrelated Native American children have one painful thing in common: juvenile Paget’s disease (JPD), an extremely rare, bone metabolism disorder. Now, researchers at Washington University School of Medicine in St. Louis and Shriners Hospitals for Children, St. Louis, have discovered that the two patients also share an unusual 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 is the first to identify a genetic cause for JPD and is published in the July 18 issue of the New England Journal of Medicine.

"By identifying this genetic defect in two people, our results not only provide insight into the cause of JPD, but also shed light on the control of bone metabolism in general," says lead investigator Michael P. Whyte, M.D., professor of medicine, genetics, and pediatrics at the School of Medicine and director of the Center for Metabolic Bone Disease and Molecular Research at Shriners Hospitals for Children. "Understanding how the skeleton forms and breaks down is key to developing ways to diagnose and treat bone disorders in children and adults, including adult Paget’s disease and osteoporosis."

JPD, also known as hereditary hyperphosphatasia or hyperostosis corticalis deformans juvenilis, has only been reported in about 40 people worldwide. It is a painful skeletal disease 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. However, JPD appears to affect all bones in the body, whereas Paget’s disease of bone involves only a select few.

The Washington University and Shriners 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 one year of age. The team later learned that a second JPD patient, described in the 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 team first evaluated the gene for RANK in these two patients. In a previous collaborative study, they had identified a RANK defect as the cause of three other rare but somewhat similar genetic bone disorders also characterized by accelerated bone metabolism. The two Navajo patients, however, had normal RANK genes.

The researchers next tested the gene that makes osteoprotegerin, a protein discovered only a few years ago. Osteoprotegerin is related functionally to RANK and recent studies have found that mice lacking the protein have a condition where 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," says Steven Mumm, Ph.D., research assistant professor of medicine at the School 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, or alleles, 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 Washington University, the team was able to pinpoint exactly where DNA had broken off in these two patients.

Again, the results were startling: The genetic damage was identical in both patients. The researchers therefore conclude that these two patients likely share a common ancestor, perhaps dating back a century.

"In a way, this also is a sociology story," says Whyte. "Our findings appear to represent the emergence of a "founder effect" in this population that underwent a "bottleneck" constriction years ago. The Navajo Nation decreased from about several hundred thousand individuals to about 6 thousand in the 1860s. As the population then re-grew, 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 these 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.

Gila Z. Reckess | EurekAlert

More articles from Health and Medicine:

nachricht Research reveals how diabetes in pregnancy affects baby's heart
13.12.2017 | University of California - Los Angeles Health Sciences

nachricht Routing gene therapy directly into the brain
07.12.2017 | Boston Children's Hospital

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Long-lived storage of a photonic qubit for worldwide teleportation

MPQ scientists achieve long storage times for photonic quantum bits which break the lower bound for direct teleportation in a global quantum network.

Concerning the development of quantum memories for the realization of global quantum networks, scientists of the Quantum Dynamics Division led by Professor...

Im Focus: Electromagnetic water cloak eliminates drag and wake

Detailed calculations show water cloaks are feasible with today's technology

Researchers have developed a water cloaking concept based on electromagnetic forces that could eliminate an object's wake, greatly reducing its drag while...

Im Focus: Scientists channel graphene to understand filtration and ion transport into cells

Tiny pores at a cell's entryway act as miniature bouncers, letting in some electrically charged atoms--ions--but blocking others. Operating as exquisitely sensitive filters, these "ion channels" play a critical role in biological functions such as muscle contraction and the firing of brain cells.

To rapidly transport the right ions through the cell membrane, the tiny channels rely on a complex interplay between the ions and surrounding molecules,...

Im Focus: Towards data storage at the single molecule level

The miniaturization of the current technology of storage media is hindered by fundamental limits of quantum mechanics. A new approach consists in using so-called spin-crossover molecules as the smallest possible storage unit. Similar to normal hard drives, these special molecules can save information via their magnetic state. A research team from Kiel University has now managed to successfully place a new class of spin-crossover molecules onto a surface and to improve the molecule’s storage capacity. The storage density of conventional hard drives could therefore theoretically be increased by more than one hundred fold. The study has been published in the scientific journal Nano Letters.

Over the past few years, the building blocks of storage media have gotten ever smaller. But further miniaturization of the current technology is hindered by...

Im Focus: Successful Mechanical Testing of Nanowires

With innovative experiments, researchers at the Helmholtz-Zentrums Geesthacht and the Technical University Hamburg unravel why tiny metallic structures are extremely strong

Light-weight and simultaneously strong – porous metallic nanomaterials promise interesting applications as, for instance, for future aeroplanes with enhanced...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

See, understand and experience the work of the future

11.12.2017 | Event News

Innovative strategies to tackle parasitic worms

08.12.2017 | Event News

AKL’18: The opportunities and challenges of digitalization in the laser industry

07.12.2017 | Event News

 
Latest News

Gecko adhesion technology moves closer to industrial uses

13.12.2017 | Information Technology

Columbia engineers create artificial graphene in a nanofabricated semiconductor structure

13.12.2017 | Physics and Astronomy

Research reveals how diabetes in pregnancy affects baby's heart

13.12.2017 | Health and Medicine

VideoLinks
B2B-VideoLinks
More VideoLinks >>>