Cause of rare growth disease discovered

Example of fatty overgrowth, affecting specific body regions, caused by mutations in the phosphatidylinositol 3 kinase PI3K (AKT) signalling pahtway. Credit: Nature Genetics.

A rare genetic disease which causes some parts of the body to grow excessively has been linked to a cancer-associated mutation that drives cell growth, potentially paving the way for new treatments.  The research findings were published today, 24 June, .

An international collaboration among the University of Cambridge, the Sanger Institute, and the Babraham Institute in the UK and the National Institute for Health in the US  has discovered that unrestrained and sometimes massive fatty ’overgrowth’ affecting only some body regions is caused by mutations in the phosphatidylinositol-3-kinase (PI3K)/AKT signalling pathway (which is critical for cellular growth and metabolism).

The types of mutations which cause these overgrowths typically arise during embryonic development.  Unlike conditions caused by genetic mutations which are transmitted from parents (in which every cell in the body is affected), in this condition only the ’offspring’ of the cell where the mutation occurs carry the change. This accounts for why only some parts of the body are affected.

The scientists from the University of Cambridge and the Sanger Institute, who were funded mainly by the Wellcome Trust, first studied a patient who had severe overgrowth of her legs but a normal upper body.  By conducting a genetic analysis of cells sampled from the affected and unaffected areas, they were able to identify a critical mutation which caused the overgrowth in her legs. Scientists at the Babraham Institute then made use of their unique lipidomics mass spectrometry capability to demonstrate abnormal activation of the signalling pathway in cells from the leg but not the arm. These studies were extended in collaboration with scientists at the US National Institute for Health in Maryland, leading to discovery of nine other patients with similar mutations, confirming the results and suggesting that activation of the PI3K pathway may be a common cause of this form of fatty overgrowth.