Researchers have identified a gene variant in the rare tissue and bone overgrowth disorder Proteus syndrome that may confirm the cause of the severe disfigurement suffered by "Elephant Man", a 19th century Englishman whom experts believe may have had the disease. Called AKT1, the gene may be a target for future therapies, bringing hope to patients and their families. You can read a scientific paper about its discovery in the 27 July early online issue of the New England Journal of Medicine.
The study was led by the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health, in the United States. NHGRI Director, Dr Eric D. Green, told the press that:
"This study resolves a daunting challenge in clinical genetics and offers hope for patients with Proteus syndrome."
The study was led by the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health, in the United States. NHGRI Director, Dr Eric D. Green, told the press that:
"This study resolves a daunting challenge in clinical genetics and offers hope for patients with Proteus syndrome."
"This rare disorder has been the focus of curiosity and medical observation for decades but until now has never been biologically explained. With the analysis reported here, patients and families who face this condition have hope for future therapies."
Proteus syndrome is a rare disorder where tissue and bone grow hugely out of proportion (Proteus is the name of the Greek god who could transform his shape). It is so rare estimates suggest there may be as few as 500 people around the world with the disorder, although it could be more, because the condition is very difficult to diagnose.
In this study, the researchers found that a single "point mutation" in the DNA of the AKT1 gene activates the sporadic tissue growth that characterizes Proteus syndrome. A point mutation is the equivalent of spelling one word differently in a large volume of text.
Proteus syndrome came to the public's attention in the 1980s through Davind Lynch's film "The Elephant Man", where John Hurt plays the part of Joseph (called John in the film) Merrick, a severely deformed Londoner discovered performing in a Victorian freak show. Experts believe Merrick may have had the disorder, and the team behind this study are planning to test DNA recovered from his skeleton to find out. Merrick died in 1890 in what is now the Royal London Hospital, where his skeleton has been preserved as part of the hospital's pathology collection.
But that will not be straightforward, because of something quite rare known as "genetic mosaicism", of which the AKT1 mutation is an example. In genetic mosaicism, the individual essentially harbours two genomes, such that a subset of the body's cells has a different genome to the rest. The AKT1 mutation behind Proteus syndrome is in one genome but not the other, so if you took biopsy samples from a person with Proteus syndrome, you could inadvertently only sample cells featuring the genome without the mutation, and conclude it wasn't present.
The AKT1 mutation in Proteus syndrome occurs spontaneously while the embryo is developing. It is not like genes that cause inherited diseases, where the mutation is passed on through the sperm or the egg. Also, the severity of the disease depends on when the "spelling mistake" occurs in a single cell in the embryo. All cells descended from that cell then inherit the mutation, and that is how the individual ends up with two genomes: the "normal" one and the one containing the mutation.
When a baby carrying the AKT1 mutation is born, he or she will appear normal at first, but during the first two years of life, the symptoms of Proteus syndrome will start showing themselves, as more and more cells with the mutation divide according to growth "rules" that are unlike those of the cells carrying the "normal" genome. Thus some parts of the child's body will start to grow and deform, sometimes massively out of proportion, while the rest of the body grows normally. This gets worse as the person gets older, and also makes them more vulnerable to tumors.
So far, the only way to diagnose the syndrome has been by observing these signs and symptoms. As well as abnormal growth, the condition causes skin lesions and thickening of the soles of the feet. Some patients also develop neurological problems, some have mental retardation, some can lose their sight.
So far, the only way to diagnose the syndrome has been by observing these signs and symptoms. As well as abnormal growth, the condition causes skin lesions and thickening of the soles of the feet. Some patients also develop neurological problems, some have mental retardation, some can lose their sight.
Senior author Dr Leslie Biesecker, chief of Genetic Diseases Research at NHGRI, said they have great difficulty diagnosing Proteus syndrome, but this molecular discovery should really help conduct diagnoses more objectively, especially in patients with "perplexing forms of overgrowth".
For the study, Biesecker and colleagues scanned the "exomes" of seven patients with Proteus syndrome. The exome is that part of the genome that controls protein production, and contains less than 2% of the 3 billion "letters" in the "text" of a whole genome, making searching for a single letter gene mutation much easier. When they found the AKT1 mutation, they then confirmed it by scanning another 20 affected patients and showed it was present in more than 90% of them. However, the researchers suspect that the ones that did not appear to carry the mutation could actually have it, but at a low level, or perhaps, because of the genetic mosaicism, the tissue samples they gave happened to contain only cells with the "normal" genome.
For the study, Biesecker and colleagues scanned the "exomes" of seven patients with Proteus syndrome. The exome is that part of the genome that controls protein production, and contains less than 2% of the 3 billion "letters" in the "text" of a whole genome, making searching for a single letter gene mutation much easier. When they found the AKT1 mutation, they then confirmed it by scanning another 20 affected patients and showed it was present in more than 90% of them. However, the researchers suspect that the ones that did not appear to carry the mutation could actually have it, but at a low level, or perhaps, because of the genetic mosaicism, the tissue samples they gave happened to contain only cells with the "normal" genome.
They also tested this the other way around: by sampling people without the syndrome. In a random study population of more than 400 individuals, not one was found to be carrying the AKT1 mutation. And neither was it present in thousands of DNA sequences stored in public genome research databases.
The gene AKT1 is an oncogene, known to cause uncontrolled growth in cancer. The mutation present in Proteus syndrome is part of a cascade of mutations that foster metastasis, where cancer cells migrate from the primary tumor to seed new tumors in other parts of the body. AKT1 mutations have been found in about 2% of cancers. Biesecker said if the mutation that occurs in Proteus syndrome were to occur very early in the development of the embryo, it would affect so many cells of the body that it would be unlikely that a person could survive for long.
The researchers found that the AKT1 mutation in Proteus syndrome is an accelerator of cell growth. Stopping its activity should then stop the overgrowth activity of the protein. Biesecker said: "We now have a better chance of making or finding a drug that can arrest this overgrowth and begin to use it early on in the disease progression."
"A factor in our favor is that it is much easier to find a drug that inhibits the activity of a protein, which is what we want to do with AKT in Proteus syndrome, than to activate a protein," he explained. "A Mosaic Activating Mutation in AKT1 Associated with the Proteus Syndrome."
Marjorie J. Lindhurst, Julie C. Sapp, Jamie K. Teer, Jennifer J. Johnston, Erin M. Finn, and others.
NEJM, online first 27 July 2011; doi:10.1056/NEJMoa1104017
Additional source: NIH.
Additional source: NIH.
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