GGC's Everman Involved in Proteus Syndrome Discovery

A team of researchers, including Dr. David Everman, Associate Clinical Geneticist at the Greenwood Genetic Center’s Greenville office, has identified the genetic mutation that causes Proteus syndrome, a rare disorder in which tissue and bone grows massively out of proportion. The discovery, which has implications for potential drug therapies and even cancer, appears in the July 27, 2011, early online edition of the New England Journal of Medicine. The team was led by researchers at the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health, with whom Everman collaborates.

Proteus syndrome gained wide public attention in 1980, through the movie "The Elephant Man," based upon the life and death of Joseph Merrick, a 19th century Londoner whom experts believe may have suffered from the disease.

Researchers found that a point mutation — a single-letter misspelling in the DNA of the genetic code — in the AKT1 gene activates the sporadic tissue growth seen in Proteus syndrome. Besides overgrowth of limbs, the condition is characterized by a variety of skin lesions and thickening of the soles of the feet. Some patients have neurological complications, such as intellectual disability, seizures and vision loss.

Unlike inherited disease-causing mutations, the gene variant that triggers Proteus syndrome occurs spontaneously in each affected individual during embryonic development. Only the cells that descend from the cell with the original AKT1 gene mutation display the hallmarks of the disease, leaving the individual with a mixture of normal and mutated cells, a phenomenon known as genetic mosaicism.  

The mutation in AKT1 alters the ability of affected cells to regulate their own growth, leading some parts of the patient’s body to grow to abnormal and even enormous sizes, while other parts of the body remain normal.

“This exciting discovery provides the foothold needed to further unravel the mysteries of Proteus syndrome at the most basic level,” said Dr. Everman. “Hopefully this will lead to improved treatment
and possibly even prevention of its many complications.”

As follow up to the current study, NHGRI researchers plan to test DNA from the skeleton of Joseph Merrick to determine whether Proteus syndrome caused his dramatic disfigurement. London Hospital, now the Royal London Hospital, where Joseph Merrick lived at the end of his life and died at age 27, preserved his skeleton in its pathology collection, providing modern researchers a chance to test his century-old DNA.

 Until now, clinical diagnosis has been based on observation of patient features. “Diagnosis in our patients has been really difficult,” said senior author Leslie Biesecker, M.D., chief of NHGRI’s Genetic Diseases Research Branch. “This molecular discovery gives us a basis for objective molecular diagnosis for patients with perplexing forms of overgrowth.”

To find the single-letter misspelling among the 3 billion letters that make up the human genome, the researchers performed whole-exome sequencing on the DNA of seven patients with Proteus syndrome. Whole-exome sequencing determines the sequence of letters that make up the 1 to 2 percent of the genome that contains protein-coding genes. The research team then analyzed more than 20 additional affected individuals, finding the same gene variant in DNA in more than 90 percent of these individuals. By contrast, the variant is never found in unaffected people, including a random study population of more than 400 individuals and in thousands of DNA sequences maintained in public genome research databases.

The mutated gene, AKT1, is an oncogene, meaning that it can promote the kind of uncontrolled cell growth associated with cancer. The variant of AKT1 that causes Proteus syndrome is part of a cascade of mutations that also promotes metastasis, the process by which cancer cells spread to healthy parts of the body. AKT1 mutations have been detected in about two percent of cancer samples.

In cancer, an AKT1 mutation develops as part of a chain of events that occurs in a limited number of normal cells of a particular organ of the body. In Proteus syndrome, because the mutation occurs in embryonic development, many more tissues of the body are impacted. In the cancer field, there are a number of potential therapeutics being developed to inhibit the pathway involving this gene, some of them by inhibiting AKT1 itself.

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