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FAH
fumarylacetoacetate hydrolase
The FAH gene provides instructions for producing the fumarylacetoacetate hydrolase enzyme, which plays a critical role in the metabolic breakdown of the amino acid tyrosine. The FAH gene is responsible for encoding the enzyme fumarylacetoacetate hydrolase.
FAH is located on the long (q) arm of chromosome 15, at band 15q25.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The FAH gene, full name fumarylacetoacetate hydrolase, plays a vital role in human metabolism by providing instructions for an enzyme involved in amino acid breakdown. This enzyme, also called fumarylacetoacetate hydrolase, is particularly abundant in the liver and kidneys, though it is found in smaller quantities throughout the body.
Disruptions to the normal function of the FAH gene can lead to metabolic disorders due to the impaired processing of specific amino acids.
What the gene does
The FAH gene encodes the enzyme fumarylacetoacetate hydrolase, which is the final enzyme in a series of five that are responsible for breaking down the amino acid tyrosine. Tyrosine is a fundamental building block of proteins found in numerous foods. Specifically, the fumarylacetoacetate hydrolase enzyme converts fumarylacetoacetate, a byproduct of tyrosine metabolism, into smaller molecules.
These smaller molecules are then either excreted from the body via the kidneys or are utilised in various metabolic pathways to produce energy or synthesise other essential substances. When the FAH enzyme is deficient or non-functional, fumarylacetoacetate and its precursors can accumulate, leading to toxic effects within the body.
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Chromosome location
The FAH gene is located on chromosome 15, specifically at position 15q25.1. This precise location on the long arm (q) of chromosome 15 helps define its genomic address within the human genome.
Protein structure
The FAH protein, fumarylacetoacetate hydrolase, consists of 419 amino acids. Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Genetic variations, known as variants, within the FAH gene can affect the production or function of the fumarylacetoacetate hydrolase enzyme. These variants can range from single nucleotide changes to larger deletions or insertions, and their impact on enzyme activity can vary significantly. Pathogenic variants typically lead to reduced or absent enzyme function, disrupting the normal metabolic pathway.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1014del | p.Gly337_Cys338insTer | Pathogenic | ★★☆☆ | Tyrosinemia type I |
c.1203C>G | p.Tyr401Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Tyrosinemia type I |
c.34T>C | p.Phe12Leu | Pathogenic/Likely pathogenic | ★★☆☆ | Tyrosinemia type I |
c.577T>C | p.Cys193Arg | Pathogenic/Likely pathogenic | ★★☆☆ | Tyrosinemia type I |
c.608del | p.Ala203fs | Pathogenic/Likely pathogenic | ★★☆☆ | Tyrosinemia type I |
c.701G>A | p.Trp234Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Tyrosinemia type I |
c.72_81dup | p.Pro28fs | Pathogenic/Likely pathogenic | ★★☆☆ | Tyrosinemia type I |
c.745C>A | p.Pro249Thr | Pathogenic/Likely pathogenic | ★★☆☆ | Tyrosinemia type I |
c.82-1G>C | - | Pathogenic/Likely pathogenic | ★★☆☆ | Tyrosinemia type I |
c.879C>A | p.Tyr293Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Tyrosinemia type I |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Variants in the FAH gene are primarily associated with hereditary tyrosinaemia type I. This condition is inherited in an autosomal recessive pattern, meaning an individual must inherit two affected copies of the gene (one from each parent) to develop the disorder. Hereditary tyrosinaemia type I is characterised by severe liver and kidney disease, neurological problems, and other symptoms that often manifest in infancy.
Inheritance pattern
Conditions caused by pathogenic FAH variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
The FAH gene is recognised in the UK by NHS England's National Genomic Test Directory. It is included on several Green RAG (Red Amber Green) rated panels, indicating that there is strong evidence for its association with specific conditions and that testing is routinely offered. These panels include Cholestasis, DDG2P, Foetal anomalies (R21), Hereditary neuropathy, Hereditary neuropathy or pain disorder (R78), Hypophosphataemia or rickets (R154), Likely inborn error of metabolism (R98), Neonatal cholestasis, Renal tubulopathies (R198), and Undiagnosed metabolic disorders.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is hereditary tyrosinaemia type I?
Hereditary tyrosinaemia type I is a serious inherited metabolic disorder caused by a deficiency of the fumarylacetoacetate hydrolase enzyme, encoded by the FAH gene. This leads to the accumulation of toxic byproducts from tyrosine metabolism, primarily affecting the liver, kidneys, and nervous system.
How is hereditary tyrosinaemia type I inherited?
Hereditary tyrosinaemia type I follows an autosomal recessive inheritance pattern. This means that an individual must inherit two altered copies of the FAH gene-one from each parent-to be affected by the condition. Individuals who inherit only one altered copy are carriers and typically do not show symptoms.
What is the function of the FAH enzyme?
The FAH enzyme, fumarylacetoacetate hydrolase, is the last in a series of enzymes responsible for breaking down the amino acid tyrosine. It converts a tyrosine byproduct called fumarylacetoacetate into smaller molecules that are either excreted or used for energy and other metabolic processes.
References
- Pérez-Carro R, Sánchez-Alcudia R, Pérez B. Functional analysis and in vitro correction of splicing FAH mutations causing tyrosinemia type I. Clinical genetics. 2014. PMID: 23895425
- Fernández-Lainez C, Ibarra-González I, Belmont-Martínez L. Tyrosinemia type I: clinical and biochemical analysis of patients in Mexico. Annals of hepatology. 2014. PMID: 24552869
- Demers SI, Russo P, Lettre F. Frequent mutation reversion inversely correlates with clinical severity in a genetic liver disease, hereditary tyrosinemia. Human pathology. 2003. PMID: 14691918
- Arranz JA, Piñol F, Kozak L. 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. Human mutation. 2002. PMID: 12203990