Normal Function
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 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.
Health Conditions Related to Genetic Changes
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.
More About This Health ConditionOther Names for This Gene
- beta-diketonase
- FAA
- FAAA_HUMAN
- fumarylacetoacetase
- fumarylacetoacetate hydrolase (fumarylacetoacetase)
Additional Information & Resources
Tests Listed in the Genetic Testing Registry
Scientific Articles on PubMed
Catalog of Genes and Diseases from OMIM
References
- Arranz JA, Pinol F, Kozak L, Perez-Cerda C, Cormand B, Ugarte M, Riudor E. Splicing mutations, mainly IVS6-1(G>T), account for 70% of fumarylacetoacetate hydrolase (FAH) gene alterations, including 7 novel mutations, in a survey of 29 tyrosinemia type I patients. Hum Mutat. 2002 Sep;20(3):180-8. doi: 10.1002/humu.10084. Citation on PubMed
- Demers SI, Russo P, Lettre F, Tanguay RM. Frequent mutation reversion inversely correlates with clinical severity in a genetic liver disease, hereditary tyrosinemia. Hum Pathol. 2003 Dec;34(12):1313-20. doi: 10.1016/s0046-8177(03)00406-4. Citation on PubMed
- Fernandez-Lainez C, Ibarra-Gonzalez I, Belmont-Martinez L, Monroy-Santoyo S, Guillen-Lopez S, Vela-Amieva M. Tyrosinemia type I: clinical and biochemical analysis of patients in Mexico. Ann Hepatol. 2014 Mar-Apr;13(2):265-72. Citation on PubMed
- Perez-Carro R, Sanchez-Alcudia R, Perez B, Navarrete R, Perez-Cerda C, Ugarte M, Desviat LR. Functional analysis and in vitro correction of splicing FAH mutations causing tyrosinemia type I. Clin Genet. 2014 Aug;86(2):167-71. doi: 10.1111/cge.12243. Epub 2013 Aug 21. Citation on PubMed
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