Gene discovery could be a skeleton key (turns muscle and tendons into bone)

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http://www.smh.com.au/articles/2006/04/24/1145861289788.html

Gene discovery could be a skeleton key

 

 

By Thomas Maugh in Los AngelesApril 25, 2006

 

Breakthrough … a scan of an affected skeleton.Photo: AP

RESEARCHERS have discovered the gene that causes one of the rarest congenital disorders, a disease called FOP that turns muscle and tendons into bone, forming a second skeleton that eventually renders the patient immobile like a statue.

The disease strikes fewer than one in every 2 million people and is so rare most doctors misdiagnose it, prescribing treatments that generally make the condition worse.

Only about 600 patients are known, and the majority of them become bedridden by their 30s. There is no treatment; removing the excess bone only makes it grow back faster.

The discovery of the FOP gene could eventually lead to the first treatments for the disease, says researcher Dr Frederick Kaplan, the University of Pennsylvania School of Medicine.

The finding, reported yesterday in the journal Nature Genetics, could lead to new treatments for other bone diseases that involve excessive or insufficient bone growth.

Other doctors have hailed the finding as a huge advance in treating the disease.

FOP, formally known as fibrodysplasia ossificans progressiva, is apparent at birth: toes are unusually short and point outward laterally. Other symptoms can begin appearing any time during the first 25 years. The first signs are typically swellings on the arm, neck or shoulders, accompanied by severe pain. The pain may fade after a few weeks, but the swellings remain.

Mobility becomes progressively worse. By the time patients are teenagers, they usually cannot raise their arms above their heads. As muscles around the lungs are converted to bone, breathing becomes more difficult. Trauma, such as bruises, injections and biopsies, accelerate the process.

"This is the only genetic disorder I know of in which one organ is converted into a different one," Dr Kaplan said. "The new bone is totally normal. It is just in the wrong place at the wrong time."

Dr Kaplan has been studying the disorder for 15 years. In that time, it became clear the problems were associated with a protein called bone morphogenetic protein, which is known to be linked to bone growth.

But finding the gene has been difficult because there are few families in which more than one generation is afflicted.

Although the gene was known to be autosomal dominant - if one parent has it, each child has a 50 per cent chance of inheriting it - most cases involve a spontaneous mutation in the patient at conception.

Dr Kaplan and his colleague Shore found five families in which the disease struck at least two generations.

In each family they identified a defective form of a gene called ACVR1, which is the blueprint for a protein that regulates bone morphogenetic protein.

A change in one nucleotide leads to a change in the protein that prevents bone morphogenetic protein from binding properly. The same nucleotide changes were found in virtually all other FOP patients.

"That's all that it takes to subvert all the control mechanisms that have developed over 400 million years of evolution," Dr Kaplan said. "The importance is that this immediately suggests a treatment strategy, although it could be years or decades before an actual treatment is found."

One patient who is looking forward to the development of a treatment is Stephanie Snow, 15, of Santa Maria, California, who has been visiting Dr Kaplan since she was two.

Stephanie can no longer lift her arms above her shoulders and has impaired mobility in her jaw and hips. "I didn't think I would see it [the gene discovery] this soon," she said. "It has given me a lot of hope."

Los Angeles Times