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‘Elephant Man’ gene found

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An international team reports discovering the mutation responsible for Proteus syndrome. This very rare and troubling developmental disorder causes severe, uncontrollable outgrowths of soft and bony tissue, leaving those affected painfully deformed. Roughly 500 people in the developed world are know to have it. Joseph Merrick (pictured) who lived from 1862 to 1890 and toured Europe as ‘The Elephant Man,’ is probably the disease’s most famous victim. The finding ends a long search for the cause of the disease and may provide some useful insight for treatment given that the gene involved, AKT1, is a well-researched target in cancer.

At a press conference announcing the results yesterday, Tracy Whitewood-Neal, of the Proteus Syndrome Foundation UK, called the finding “the light at the end of the tunnel and the hope that we’ve been dreaming of for many years”. She is a co-author on the paper and the mother of a 16 year old boy, Jordan, who has Proteus syndrome.

Leslie Biesecker at the National Human Genome Research Institute in Bethesda, Maryland, and several colleagues had been studying the syndrome for more than 15 years, performing surgeries to reduce the outgrowths for patients and retaining, with permission, the samples.

Biesecker and colleagues sequenced the protein coding DNA regions – or exomes – from tissue samples collected for six affected individuals. They also sequenced DNA from non-affected tissue. That’s because the disease had been hypothesized to express what is known as genetic mosaicism: the mutation likely arises in just one or a few cells of a developing embryo and as a result only some parts of the body carrying it are affected – those that came from the original mutant cell population. But they cast a wide net, also sequencing several patients’ parents and an unaffected identical twin. “All bets were off in terms of what kind of a genomic aberration could cause this disorder,” said Biesecker at the press conference.

In almost all the affected tissues, they found a single nucleotide change in the gene AKT1; it did not appear in non-affected tissues, confirming the mosaicism hypothesis. They then tested tissue samples from 29 other individuals diagnosed with Proteus syndrome and found the same exact mutation in all but three of them. The mutation, in a protein that helps control cell cycle and growth, appears to overactivate the protein. It was gratifying, says Biesecker, that AKT1 turns out to be in the same regulatory pathway as the gene PTEN,** which has previously been associated with Proteus-like syndromes that at times were confused with the disorder. It helps explain the clinical overlap.

Moreover, the mutation is a known, but rare, cause of some cancers. The activity of the gene has been studied extensively in mice, and some researchers have derived drugs targeting the protein “There’s still much to do,” Biesecker says, especially given that Proteus syndrome isn’t a cancer. “The trick will be to balance slowing down the mutation in the overactive cells without affecting the activity of the protein in normal cells, which might have connotations for health.”

The group now hopes to sequence DNA from Merrick, in hopes of determining once and for all if he had Proteus syndrome or some related disorder. The Royal London Hospital, where Merrick died at age 27, still has his bones and have granted access to the group to try and extract DNA. They hope to have results within a few months.

** UPDATE: In reporting this story, I had requested comments from Deborah Marsh at the University of Sydney in Australia. Marsh and her colleagues had previously argued in the literature with Biesecker and his colleagues about the diagnosis of some patients with a PTEN mutation. The Australian group has maintained that Proteus syndrome is an accurate diagnosis for some of these individuals. Incidentally, they had also reported successfully treating a patient with a PTEN mutation with the drug rapamycin, an immune suppressant that targets proteins in pathways affected by both PTEN and AKT1 (researchers have been investigating the drug for its anti-cancer potential as well). Marsh says she would have liked to see some discussion of these results in the current paper from Biesecker’s group. Biesecker wrote via email that he was aware of the report. “Until recently, there was no rational basis for doing this in proteus, so I was skeptical. That proteus is in the same pathway as this disorder (which I would call SOLAMEN or type 2 segmental Cowden syndrome, which we mentioned in our paper) would say there is now a rational basis for this.” He does urge caution however that rapamycin only targets some of the effects of AKT1 and PTEN, so a more broadly acting drug might be in order. Of course a more broadly acting drug might be more toxic.

Image: Royal London Hospital Archives via Wikimedia commons

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    mahnaz asadi said:

    hello.i need help you.i have a son.he is 5years old.he has proteos syndrom.i leave in the iran.please help me and my son.

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    mahnaz asadi said:

    excuse me ,i dont knowe english very well.i hope help me for persistent of sydney university for cure my son.im so happy when read this article.if you want i can send documents my son for you.in my country any action for this syndrom.I live in the iran .tanke you.

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