Point mutation caused a freak side-show

The Proteus syndrome, a rare disorder in which tissue and bone grows massively out of proportion, was named after the Greek god who could transform his shape at will. Joseph Merrick, a 19th century Londoner who is thought to have suffered from the disease, had no such choice. His attempts to regain the dignity he lost after years spent as a side-show freak were portrayed by John Hurt in the 1980 film, ‘The elephant man’.

Merrick’s skeleton is preserved at the Royal London Hospital, where researchers plan to examine his DNA to confirm whether he did indeed suffer from Proteus syndrome. However, the condition is difficult to diagnose because only a subset of the body’s cells are affected, in a process known as genetic mosaicism. The patient effectively develops more than one genome which can result in a missed diagnosis if only “normal” cells are sampled during a medical biopsy.

A team led by researchers at the National Human Genome Research Institute, part of the US National Institutes of Health, have identified the gene variant — a point mutation in the AKT1 gene — that triggers Proteus syndrome. Unlike inherited disease-carrying mutations this one occurs spontaneously during embryonic development. The affected newborn appears normal but symptoms arise as cells that are descended from the cell with the original mutation grow to abnormal size while other parts of the body remain normal.

This research may lead to a drug that can arrest the overgrowth but may also have implications for cancer research. The mutated gene AKT1 is an oncogene that can promote uncontrolled cell growth.

Furthermore the variant that causes Proteus syndrome appears to be part of a cascade of mutations that promotes metastasis, the process by which cancer cells spread to healthy parts of the body.

A number of potential treatments are now being developed to inhibit the chain of mutation events involving AKT1 or to inhibit the gene itself.