Genetic clue to 'Elephant Man' condition

Behind the Headlines

Friday July 29 2011

Joseph Merrick had Proteus syndrome

The Independent today reported that scientists may have discovered the genetic cause of Proteus syndrome, the rare condition made famous by Joseph Merrick, whose life was portrayed in the film The Elephant Man. Born in 1862, Merrick had progressive facial and limb deformities that were characteristic of his condition.

Proteus syndrome, which affects less than one in a million people, causes overgrowth or enlargement of multiple tissues and organs, and raises the risk of a person developing tumours. It is thought that the growths are caused by genetic mutations arising within a cell in the body, which divides and grows into areas of mutated tissue.

This new research analysed the genetic make-up found within the cells of patients with Proteus syndrome, comparing how affected and unaffected areas differed. Researchers discovered that 90% of individuals with the condition had a specific mutation in the AKT1 gene in some of their cells.

The results from this study support the conclusion that a specific mutation in the AKT1 gene causes Proteus syndrome. Ideally, other studies will confirm these results in a larger number of cases, as so far this study has examined 29 patients. However, as the disease is so rare, it is likely to be difficult to identify large numbers of patients. This work will help researchers to understand the biology of the disease better, and may help in the diagnosis of Proteus syndrome.


Where did the story come from?

The study was carried out by researchers from the US National Human Research Institute and other research institutes worldwide. It was funded by the Intramural research programme of the US National Human Genome Research Institute and the Proteus Syndrome Foundations in the United States and the United Kingdom. The study was published in the peer-reviewed New England Journal of Medicine.

The Independent covered this story accurately.


What kind of research was this?

This was a case-control study that aimed to identify differences in the genetic make-up of cells from people with a rare condition called Proteus syndrome (cases) and people without the condition (controls). This is an appropriate study design for identifying genetic mutations that might be responsible for Proteus syndrome.

Proteus syndrome is a condition in which there are uneven areas of overgrowth or enlargement of multiple tissues and organs in the body, along with an increased susceptibility to the development of tumours. It is a rare disorder, with less than one person per million affected. It is thought to be caused by genetic mutation, with the mutation occuring soon after an embryo is formed (instead of being hereditary). This mutation is believed to occur in a somatic cell within the embryo: a somatic cell forms part of the body but is not one of the reproductive cells (in other words, it is not an egg or a sperm). Only this particular cell and the cells that arise from it will have this mutation, and other cells in the body will not carry it, which means that different cells within the same person will have different genetic sequences. Having different genetic sequences in different parts of the body causes individuals with Proteus syndrome to have “affected” and “unaffected” parts of their bodies.


What did the research involve?

The researchers obtained blood and tissue samples from 29 people with Proteus syndrome and people without the condition (controls). They then compared the genetic make-up of these samples.

The researchers took samples from both affected and unaffected areas of individuals with Proteus syndrome and analysed the sequences of all known genes in each sample. Affected areas were considered to be those that had visible signs of overgrowth or blood vessel anomalies, while unaffected samples were taken from areas of the body that did not have these signs. Unaffected tissue samples were sourced from areas that were as far from the affected areas as possible. This analysis was initially performed on DNA samples from six people with Proteus syndrome and six unaffected controls. The control samples were obtained from the parents and one unaffected twin of the individuals with Proteus syndrome.

The researchers compared the samples’ DNA sequences to look for genetic variations that were present in the affected tissues from people with Proteus syndrome but appeared less often or not at all in their unaffected tissues, and were not present in the DNA from unaffected controls. They focused on genetic variations that would affect the proteins produced by the cells.

The researchers then confirmed their initial observations by analysing more DNA samples. In total, they looked at 158 DNA samples from 29 patients with Proteus syndrome.

Once they identified a suitable candidate mutation, they also looked at how this mutation affected the protein made from the gene in question.


What were the basic results?

The researchers initially identified a mutation in the AKT1 gene that was present in the affected tissue samples, but not the unaffected tissue sample, from one individual with Proteus syndrome. This mutation would be expected to lead to an alteration of one of the amino acid “building blocks” that would be found within the AKT1 protein. This protein is involved in various processes, including the division process cells undergo to form new cells.

The researchers then looked for this mutation in cells and tissue samples from control individuals. None of the controls carried this AKT1 mutation. When the researchers analysed more cells and uncultured tissue samples from 29 patients with Proteus syndrome, they found that 26 of the 29 patients (90%) carried the mutation in the AKT1 gene in at least some of their tested cells and tissues.

However, three patients with typical Proteus syndrome did not carry the mutation. The researchers say that they only analysed between one and three samples from each of these patients, and that it was likely that these samples were negative by chance, as not every cell in an affected individual carries the mutation.

The researchers then demonstrated that this mutation causes the AKT1 protein to become “locked” in its active state; in other words, the form it would be found in when performing a function. They also note previous studies, which have found that mice genetically engineered to have an abnormally activated form of this protein display symptoms similar to Proteus syndrome.

Finally, they report that this mutation was previously found in the cells of some human cancers.


How did the researchers interpret the results?

The researchers concluded that some of the tissues of people with Proteus syndrome contain a mutation in the AKT1 gene that alters the activity of the AKT1 protein. They say that their findings, along with what is already known about AKT1, suggest that: “[constant] activation of the protein underlies the overgrowth and tumour susceptibility in these patients”.



This study has shown that mutations in the AKT1 gene are present in the affected tissues and cells from the majority of the patients tested, but are not present in samples from unaffected individuals. These results support the suggestion that the identified mutation in AKT1 could be causing the characteristic problems seen in Proteus syndrome.

So far, this study has examined 29 patients with the syndrome, and ideally other studies will confirm this result in a larger number of cases. But given the rarity of the condition, which affects fewer than one in every million people, it may be difficult to gather a larger sample population.

The knowledge gained from this study will help researchers to understand the biology of Proteus syndrome better, and may help in diagnosing it.

Analysis by Bazian

Edited by NHS Choices

Links to the headlines

Scientists discover genetic key to Elephant Man's disfigurement. The Independent, July 28 2011

Links to the science

Lindhurst MJ, Sapp JC, Teer JK et al. A Mosaic Activating Mutation in AKT1 Associated with the Proteus Syndrome. NEJM, July 28 2011


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