LIVERMORE, Calif. Scientists have tracked down the biological trigger that gives rise to Van Buchem disease, a hereditary, disfiguring bone disorder that can cause blindness and deafness. The findings provide insight into long-range gene regulation and could lead to new treatments for osteoporosis and other crippling bone disorders.

A research team from Lawrence Livermore and Lawrence Berkeley national laboratories, the Novartis Institutes for BioMedical Research in Switzerland, and the DOE Joint Genome Institute in Walnut Creek, Calif., characterized a human mutation associated with the malfunctioning of the sclerostin, or SOST, gene, and showed that it plays a key role in regulating bone formation. The culprit is a regulatory element in a missing 52,000-base-pair stretch of DNA that normally directs the SOST gene to produce a protein that maintains control of bone formation rates. Without this regulator, bone production goes up, progressively increasing bone density, or osteosclerosis.

The effect primarily occurs in the skull and lower jaw of Van Buchem patients, causing facial distortions and pinching cranial nerves, which can lead to deafness and blindness. Collarbones, ribs and long bones can also be affected.

The research team, led by Gabriela Loots of Livermore's Genome Biology Division, reports its findings today in the online version of the journal Genome Research.

Noncoding DNA segments long stretches of DNA that do not code for proteins and were once thought to have no biological function are now being found to contain regions that play a key role in switching distant genes on and off. Today's study is one of the first to pinpoint a disease-associated mutation that alters one of these long-range regulatory elements.

"Our study addresses a fundamental issue with regard to the majority of the human genome that is noncoding in nature, and its potential impact on human health," Loots said. "Noncoding regions locate
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Contact: Charlie Osolin
osolin1@llnl.gov
925-422-8367
DOE/Lawrence Livermore National Laboratory
16-Jun-2005

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