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Gene Mutation Causes Cirrhosis

Medical researchers at the Christchurch School of Medicine and Christchurch Hospital have recently determined how a gene mutation in a blood protein called fibrinogen causes a form of cirrhosis of the liver. This discovery in their two-year investigation marks an important step in understanding liver cirrhosis and the part that abnormal genes play in the pathology of this condition.

The research was led by Dr Stephen Brennan, who was involved in similar research 18 years ago on the blood protein Alpha-1 Antitrypsin where mutations also cause liver cirrhosis.

"We became interested in fibrinogen because we had the scientific background in this area, and we suspected that there was something happening in the fibrinogen molecule which was similar to what happened in Alpha-1 Antitrypsin," he says.

Fibrinogen is the protein that causes blood to coagulate. Usually it passes freely from the liver, where it is made, to the blood, but in some patients this does not occur, and instead it accumulates in the liver, eventually causing cirrhosis. This accumulation also causes deficiency in clotting because of a consequent lack of fibrinogen in the blood stream. Using sophisticated scientific techniques developed in the Molecular Pathology Laboratory at the Christchurch School of Medicine, Brennan examined the structure of this protein, and discovered a mutation in the gene which causes it to accumulate in the liver.

"The aberrant protein misfolds as it is being manufactured and the defective product cannot be exported out of liver cells," he explains. "This gradually leads to a deterioration of the liver and eventual cirrhosis, which can be fatal."

The Christchurch researchers, including Dr Peter George and Jane Wyatt, have been collaborating with internationally renowned liver pathologist Professor Callea from Brescia in Northern Italy. While the original patient from which liver samples were taken has now died from cirrhosis, the group has identified other carriers of the gene mutation, which puts them at risk. There are also families in this country who have been identified with similar problems.

Brennan says the Molecular Pathology Laboratory's achievement means it will now be easier to identify other family members who have the rogue fibrinogen gene. This will make it easier for doctors to diagnose and apply earlier and more appropriate clinical interventions than in the past.