FAH

The FAH gene provides instructions for making an enzyme called fumarylacetoacetate hydrolase. This enzyme is abundant in the liver and kidneys, and smaller amounts are found in many tissues throughout the body. Fumarylacetoacetate hydrolase is the last in a series of five enzymes needed to break down the amino acid tyrosine, a protein building block found in many foods. Specifically, fumarylacetoacetate hydrolase converts a tyrosine byproduct called fumarylacetoacetate into smaller molecules that are either excreted by the kidneys or used in reactions that produce energy.

tyrosinemia - caused by mutations in the FAH gene

Researchers have identified more than 40 FAH mutations that cause type I tyrosinemia. The altered FAH gene produces an unstable or inactive enzyme, which results in reduced or absent fumarylacetoacetate hydrolase activity. The most common FAH mutation disrupts how genetic information is spliced together to make the blueprint for producing fumarylacetoacetate hydrolase. This particular mutation, called a splice-site mutation, is written as IVS12 + 5G>A. Without sufficient fumarylacetoacetate hydrolase activity, tyrosine is not processed completely. Instead of being converted to harmless molecules, fumarylacetoacetate, a tyrosine byproduct, accumulates in the liver and kidneys. Elevated levels of fumarylacetoacetate are thought to be toxic and to cause the liver and kidney problems characteristic of type I tyrosinemia. Individuals with this disorder are also at risk of liver cancer (hepatocarcinoma). Research studies suggest that elevated levels of fumarylacetoacetate in liver cells initiate or promote tumor development.

In several cases of type I tyrosinemia, the FAH gene mutation has been observed to revert to the normal state in some liver cells. If enough cells have the reverted gene, some fumarylacetoacetate hydrolase activity is restored. Researchers have found a correlation between the severity of symptoms and the extent of reversion in liver cells. People with severe symptoms of type I tyrosinemia have few reverted cells, while those with milder symptoms have many cells with the reverted FAH gene.