Encyclopedia
Fumarylacetoacetate hydrolase: The FAH gene provides instructions for making an enzyme called fumarylacetoacetate hydrolase.
- genes
1. Normal Function
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 that work 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 to produce energy or make other substances in the body.
2. Health Conditions Related to Genetic Changes
2.1 Tyrosinemia
At least 86 FAH mutations have been found that cause tyrosinemia type I. This condition is characterized by severe liver and kidney disease, neurological problems, and other signs and symptoms that begin in infancy. The altered FAH gene that causes this condition produces an unstable or inactive enzyme, which results in reduced or absent fumarylacetoacetate hydrolase activity. The most common FAH mutation disrupts the way the gene's instructions are used to make the enzyme. This mutation (written IVS12 + 5G>A) is called a splice-site mutation and results in an abnormally short enzyme. Without sufficient fumarylacetoacetate hydrolase activity, tyrosine and its byproducts are not properly broken down. As a result, fumarylacetoacetate accumulates in the liver and kidneys. Elevated levels of fumarylacetoacetate are thought to be toxic to cells and accumulation of this substance likely causes the liver and kidney problems and other features that are characteristic of tyrosinemia type I.
In several cases of tyrosinemia type I, the FAH gene mutation has been observed to revert to the normal state in some liver cells. If enough cells have the reverted gene, which produces normal fumarylacetoacetate hydrolase, some level of enzyme activity is achieved. Researchers have found a correlation between the severity of symptoms and the extent of reversion in liver cells. People with severe symptoms of tyrosinemia type I have few reverted cells, while those with milder symptoms have many cells with the reverted FAH gene.
3. Other Names for This Gene
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beta-diketonase
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FAA
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FAAA_HUMAN
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fumarylacetoacetase
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fumarylacetoacetate hydrolase (fumarylacetoacetase)
This entry is adapted from the peer-reviewed paper https://medlineplus.gov/genetics/gene/fah
References
- Arranz JA, Piñol F, Kozak L, Pérez-Cerdá C, Cormand B, Ugarte M, Riudor E.Splicing mutations, mainly IVS6-1(G>T), account for 70% of fumarylacetoacetatehydrolase (FAH) gene alterations, including 7 novel mutations, in a survey of 29 tyrosinemia type I patients. Hum Mutat. 2002 Sep;20(3):180-8.
- Demers SI, Russo P, Lettre F, Tanguay RM. Frequent mutation reversioninversely correlates with clinical severity in a genetic liver disease,hereditary tyrosinemia. Hum Pathol. 2003 Dec;34(12):1313-20.
- Fernández-Lainez C, Ibarra-González I, Belmont-Martínez L, Monroy-Santoyo S,Guillén-López S, Vela-Amieva M. Tyrosinemia type I: clinical and biochemicalanalysis of patients in Mexico. Ann Hepatol. 2014 Mar-Apr;13(2):265-72.
- Pérez-Carro R, Sánchez-Alcudia R, Pérez B, Navarrete R, Pérez-Cerdá C, Ugarte M, Desviat LR. Functional analysis and in vitro correction of splicing FAHmutations causing tyrosinemia type I. Clin Genet. 2014 Aug;86(2):167-71. doi:10.1111/cge.12243.
