NEW YORK (GenomeWeb News) –The rare and sometimes profoundly disfiguring disease Proteus syndrome – which is believed to be have afflicted the late19th Century man who came to be called the 'Elephant Man' – is caused by a single mutation in one gene, the National Human Genome Research Institute said Wednesday.
Using next-generation sequencing and analysis technologies, NHGRI researchers and their collaborators found that an activating mutation in the AKT1 gene during fetal development is responsible for the rare disease, which affects fewer 500 people in the developed world, where it is tracked. Their research is published this week in the online edition of the New England Journal of Medicine.
Proteus syndrome, named for the shape-changing sea god of Greek mythology, causes a person's bone and flesh in certain affected areas to grow irregularly, uncontrolled, and potentially to enormous sizes, while it leaves other areas completely unaffected.
"Unlike the sea god, who could select his form, the bodies of Proteus patients change against their will because a single letter is altered among the billions of letters that make up their genetic code," NHGRI Director Eric Green said in a call with reporters.
When researchers at the NHGRI Intramural Sequencing Center conducted whole-exome sequencing using the Illumina GAIIx on seven people who have the syndrome and then performed genomic analysis of 20 more affected patients, they found the AKT1 mutation in 90 percent of them. The average number of sequence reads for each exome was nearly 96.5 million, with an average of nearly 8.6 billion bases per sample. The researchers used Agilent's All Exon kit in preparation of the sequencing.
Because they failed to find the mutation in any unaffected people, the scientists suspect that the three individuals who have the syndrome but tested negative for the mutation have it in low levels or in different tissues than were submitted for biopsy.
The research team, which was led by Chief of NHGRI's Genetic Diseases Research Branch Leslie Biesecker, found that the later in fetal development the mutation occurs, the less the body will be affected because many more of their cells will be normal than mutated. However, a mutation very early in embryonic development would probably catastrophically affect the embryo and it would not survive.
"The AKT1 gene mutation has never been found in unaffected people, as our survey included several genomic databases and other populations we study here at NIH," Biesecker explained.
"The mutation is not inherited; instead it occurs anew in a single cell in each affected individual during embryonic development, and the severity of the disease depends on when during embryonic development the mutation arises," he added.
The tissue samples used in the research came from participants who came to the NIH Clinical Center, some of them to have bone and tissue removed or to be operated on to impair its growth, Biesecker, who began studying the syndrome 15 years ago, explained in the conference call.
The gene alteration causes the abnormally active AKT protein to be created, increasing cell growth and preventing them from dying when they naturally would, leading to tumors as well as uncontrolled and accelerated tissue growth.
"This study resolves a daunting challenge in clinical genetics and offers hope for patients with Proteus syndrome," NHGRI Director Eric Green said in a statement. "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."
Biesecker said the researchers were unsure about what kind of mutation they were looking for when they dove into the exome sequencing and analysis.
"All bets were off as far as what kind of a genomic aberration could cause this disorder," he said. "It could have been a point mutation. It could have been a large genomic aberration such as a copy number variant or a structural genomic variant. It could have been a change in the imprinting or methylation or histone modification of a gene. There was just no way to know in advance, so therefore we worked our way through a number of variations."
The NHGRI researchers now hope to firmly diagnose Joseph Merrick, who lived a short life as the 'Elephant Man' novelty attraction in London and died in 1890 at the age of 27, by testing his DNA. His skeleton has been preserved by the Royal London Hospital, where he spent the end of his life.
Because diagnosing the disease so far has been based on the observation of physical features, using genomic analysis of a 120 year-old bit of skeleton to nail down a variant as the cause of Merrick's illness would be an important moment in the history of this disease, and perhaps rare disease research in general.
But the NHGRI researchers have higher ambitions – they believe the AKT1 variation could lead to a treatment or cure.
"Research on this gene mutation in cancer may turn out to be beneficial for patients with Proteus syndrome," Biesecker said.
"Work that 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 [using therapies that were] originally developed for cancer. There are a number of other potential drugs being developed to inhibit the pathway involving this gene."
Green also believes that discoveries about Proteus could provide important discoveries for cancer researchers, helping support the case for the value of studying rare and neglected diseases.
In addition to NIH funding, the research was supported by funding and other assistance by the Proteus Foundation of the US and the Proteus Foundation of the UK.