New Answers on Rare Childhood Disease

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Children born with multiple hereditary exostoses (MHE) suffer from abnormal growths on their bones. These bony protrusions stunt their growth and can cause pain and disfigurement. Scientists have long known which genes are mutated in this rare disease, but not how the mutations lead to abnormal bone growth. Even attempts at replicating the symptoms in mice have been unsuccessful, hampering the search for treatments. In a study published May 31 in Proceedings of the National Academy of Sciences USA, researchers at Sanford-Burnham Medical Research Institute (Sanford-Burnham) and their colleagues created a new mouse model that mimics the disease in humans, providing new opportunities to test treatments.

“MHE is not usually deadly, but it is debilitating,” said Yu Yamaguchi, M.D., Ph.D., senior author of the study and professor in the Sanford Children’s Health Research Center at Sanford-Burnham. “And if not removed by surgery, there is a chance these bone growths will become cancerous.”

In humans, MHE is caused by a mutation in one of two genes, Ext1 or Ext2. Together, these genes encode an enzyme necessary to produce heparan sulfate—a long sugar chain that facilitates cell signals that direct bone cell growth and proliferation.

But when these genes were inactivated in mice just as they are in human MHE patients, the mice failed to develop the symptoms of MHE. This had scientists scratching their heads.

Enter Dr. Yamaguchi and his colleagues, who took a different approach. Instead of knocking out the Ext1 gene in the whole mouse, they targeted the gene only in bone cells. Moreover, they deleted the gene in only a small fraction of these cells. Surprisingly, this minimalistic approach led to a mouse with all the physical manifestations of MHE, such as bony protrusions, short stature and other skeletal deformities.

The new mouse model answered some long-standing questions about MHE. Scientists had gone back and forth on whether the abnormal growths observed in MHE are true tumors or just malformations of the bone. In this study, the protrusions were made up of two cell types. A minority were mutant cells lacking Ext1, but, amazingly, most were normal bone cells. True tumors, in the strictest sense, arise from the proliferation of mutant cells only. Hence, MHE bone protrusions must result from a different – though still very serious – type of growth.

“I have been waiting 13 years for this breakthrough,” said Sarah Ziegler, vice president of The MHE Research Foundation, which has provided seed funding for Dr. Yamaguchi’s research. “My son had more than a 100 of these tumors and has gone through 15 surgeries. When your child has such a debilitating condition, and you know there’s nothing you can do, it’s petrifying. Now we have hope.”

While this study takes MHE research a giant step forward, more questions remain. For one, it is still unknown how a few mutant bone cells can convince normal cells to divide and proliferate abnormally. Researchers hope that this MHE model will help solve that mystery, as well as provide leads for new treatments.

“This new mouse system also provides a platform for screening potential drugs that inhibit bone growths in MHE,” Dr. Yamaguchi explained. “We are currently developing chemical inhibitors to block their formation.”

Original paper:
Matsumoto K, Irie F, Mackem S, Yamaguchi Y. A mouse model of chondrocyte-specific somatic mutation reveals a role for Ext1 loss of heterozygosity in multiple hereditary exostoses. Proceedings of the National Academy of Sciences USA. Epub 2010 May 31.

About Sanford-Burnham Medical Research Institute
Sanford-Burnham Medical Research Institute (formerly Burnham Institute for Medical Research) is dedicated to discovering the fundamental molecular causes of disease and devising the innovative therapies of tomorrow. Sanford-Burnham, with operations in California and Florida, is one of the fastest-growing research institutes in the country. The Institute ranks among the top independent research institutions nationally for NIH grant funding and among the top organizations worldwide for its research impact. From 1999 – 2009, Sanford-Burnham ranked #1 worldwide among all types of organizations in the fields of biology and biochemistry for the impact of its research publications, defined by citations per publication, according to the Institute for Scientific Information. According to government statistics, Sanford-Burnham ranks #2 nationally among all organizations in capital efficiency of generating patents, defined by the number of patents issued per grant dollars awarded.

Sanford-Burnham utilizes a unique, collaborative approach to medical research and has established major research programs in cancer, neurodegeneration, diabetes, and infectious, inflammatory, and childhood diseases. The Institute is especially known for its world-class capabilities in stem cell research and drug discovery technologies. Sanford-Burnham is a nonprofit public benefit corporation.

Source:  Sanford-Burnham Medical Research Institute

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