Chasing the 'Elephant Man': NHGRI researchers identify genetic mutation that causes Proteus Syndrome

BETHESDA, Md.—Many people have heard of Joseph Merrick, the 19^th Century Englishman with severe deformities known as the "Elephant Man." Now, more than 100 years later, some of the curiosity surrounding Merrick's condition has been satisfied, as a team of U.S. researchers have identified the genetic mutation that causes what is now commonly known as Proteus Syndrome.

The research team, led by scientists at the National Human Genome Research Institute (NHGRI), found that a point mutation in the AKT1 gene activates the sporadic tissue growth characteristic of Proteus Syndrome. According to the researchers, who published their findings in the July 27 online edition of the New England Journal of Medicine, their findings have implications for both drug therapies—and even cancer.

Proteus Syndrome became part of the public vernacular in the 1980s due to the popularity of the movie "The Elephant Man," which was based on Merrick's life. Named after the Greek sea god Proteus, who could change his shape, the condition is a congenital disorder that causes skin overgrowth and atypical bone development, often accompanied by tumors over half the body.

Only about 500 cases of Proteus Syndrome have been confirmed in the developed world, perhaps because diagnosis is typically difficult. Clinical diagnosis is usually based on an observation of patient features, such as limb overgrowth, skin lesions and thickening of the soles of the feet. Some patients also present neurological complications, such as mental retardation, seizures and vision loss.

"Unlike the sea god who could select his form, the bodies of Proteus Syndrome patients change against their will because of a single letter that is altered among the billions of letters that make up their genetic code," said Eric Green, director of the NHGRI, in a telecast briefing about the agency's study. "This single letter change causes parts of their bodies to grow out of control, becoming misshaped, enlarge and painful. For many, it is life-shortening."

The NHGRI, which focuses on rare diseases with significant unmet medical need, has been probing the cause of Proteus Syndrome for 15 years. According to Dr. Leslie Biesecker, chief of Genetic Disease Research in the NHGRI's Intramural Research Program, with the advent of next-generation sequencing, it became affordable to send DNA from biopsied tissue to the National Institutes of Health (NIH) Intramural Sequencing Center, where the team performed whole-exome sequencing on seven patients affected with Proteus Syndrome.

Whole-exome sequencing analyzed just the protein coding sequence of the genes, allowing the researchers to discover a point of mutation, a single letter misspelling in the three billion letters of the genome DNA in a gene called AKT1. This activates the sporadic tissue growth in patients with Proteus Syndrome, according to the researchers.

"A more standard sequencing strategy then went on that same gene mutation in an additional 20 affected individuals, and I really want to emphasize that all patients so far have exactly the same mutation in the same genome," Biesecker explained in the telecast. "The AKT1 gene mutation has never been found in unaffected people as our survey of several genomic databases in other populations we study here in NIH."

Of surprise to the researchers was the discovery that the mutation is not inherited, but instead occurs anew in a single cell in each affected individual during embryonic development. The severity of the disease, Biesecker explained, depends on when during embryonic development the mutation arises.

"The consequence is that only some of the body's tissues and bones displayed the overgrowth and other parts of the body are not affected," he added. "The affected patients are thus a mixture. Parts of them have the disease and parts of them do not. This makes sense biologically with what we know about this gene."

Moreover, the AKT1 gene mutation creates an oncogene, the kind of mutation that can drive uncontrolled cell division normally associated with cancer—in fact, the AKT1 mutation has been found among a group of mutations that cause cancer to spread, Biesecker said. Thus, the research on this gene mutation in cancer may turn out to be beneficial for patients with Proteus Syndrome.

"Work has been done by others to inhibit the activity of mutated AKT1 has shown that it may become possible to treat patients with Proteus Syndrome with a drug originally developed for cancer," Biesecker said. "There are a number of other potential drugs being developed to inhibit the pathway involving this gene."

However, Biesecker cautioned that "there's still much to do with respect to the fact that Proteus Syndrome isn't cancer."

"It's an overgrowth disorder, and so it will be a challenge to adapt treatment which are designed for cancers to work for overgrowth because again, these patients are mosaics and part of their body has this mutation and part does not," he explained. "So the trick will be to have a treatment that balances slowing down the mutation in the overactive cells without excessively swelling or inhibiting the activity of that protein in the normal unaffected cells which would probably have negative connotations for their health."

As follow up to the current study, the NHGRI team plans to test DNA from the skeleton of Merrick to determine whether Proteus syndrome caused his dramatic disfigurement.

The NHGRI is part of the NIH. Much of the funding and patient samples for the study came from the Proteus Syndrome Foundations in the United States and the United Kingdom.