Alternative titles; symbols
HGNC Approved Gene Symbol: FAH
SNOMEDCT: 124536006, 410056006;
Cytogenetic location: 15q25.1 Genomic coordinates (GRCh38) : 15:80,152,789-80,186,949 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q25.1 | Tyrosinemia, type I | 276700 | Autosomal recessive | 3 |
The enzyme fumarylacetoacetate hydrolase (FAH; EC 3.7.1.2) is the last enzyme in the catabolic pathway of tyrosine (summary by Tanguay et al., 1990).
Phaneuf et al. (1991) isolated human FAH cDNA clones by screening a liver cDNA expression library with specific antibodies and plaque hybridization with a rat FAH cDNA probe. From transient expression in transfected mammalian cells, a single polypeptide chain encoded by the FAH gene appeared to contain all the genetic information required for functional activity, indicating that the dimer found in vivo is a homodimer.
Grompe et al. (1993) stated that Fah is predominantly expressed in liver and kidney in mice.
By in situ hybridization, Berube et al. (1989) assigned the FAH gene to chromosome 15q23-q25. Using in situ hybridization, Tanguay et al. (1990) confirmed the assignment to chromosome 15 by analysis of rodent-human hybrid cells.
By study of somatic cell hybrids and by in situ hybridization using the FAH cDNA, Phaneuf et al. (1991) demonstrated that the gene maps to chromosome 15q23-q25.
Jorquera and Tanguay (2001) reported that a subapoptogenic dose of fumarylacetoacetate, the mutagenic metabolite accumulating in hereditary type I tyrosinemia, induced spindle disturbances and segregational defects in both rodent and human cells. A sustained activation of the extracellular signal-regulated protein kinase (ERK; see MAPK1, 176948) was also observed. Primary skin fibroblasts derived from type I tyrosinemia patients not exogenously treated with fumarylacetoacetate showed similar mitotic-derived alterations and ERK activation. Replenishment of intracellular glutathione (GSH) with GSH monoethylester abolished ERK activation and reduced the chromosomal instability induced by fumarylacetoacetate by 80%. The authors speculated that this tumorigenic-related phenomenon may rely on the biochemical/cellular effects of fumarylacetoacetate as a thiol-reacting and organelle/mitotic spindle-disturbing agent.
Tanguay et al. (1990) analyzed the FAH in livers of unrelated patients with tyrosinemia type I (TYRSN1; 276700) using mRNA levels, immunoreactive protein, and enzyme activity. They demonstrated a missense mutation in the FAH gene in cDNA from 1 patient with normal FAH mRNA but without immunoreactive protein or enzymatic activity. In the full article of this work (Phaneuf et al., 1992) stated that the mutation was an asn16-to-ile (N16I) substitution (613871.0001) in a French Canadian patient.
Grompe et al. (1994) found that 100% of tyrosinemia type I patients from the Saguenay-Lac-Saint-Jean region of Quebec and 28% of TYRSN1 patients from other regions of the world carry a splice donor site mutation in intron 12 of the FAH gene (613871.0003). Of 25 patients from the Saguenay-Lac-Saint-Jean region, 20 were homozygous. The frequency of carrier status, based on screening of blood spots from newborns, was about 1 per 25 in that region of Quebec and about 1 per 66 overall in Quebec. Using cDNA probes for the FAH gene, Demers et al. (1994) identified 10 haplotypes with 5 RFLPs in 118 normal chromosomes from the French Canadian population. Among 29 children with hereditary tyrosinemia, haplotype 6 was found to be strongly associated with disease, at a frequency of 90% as compared with approximately 18% in 35 control individuals. This frequency increased to 96% in the 24 patients originating from the Saguenay-Lac-Saint-Jean region. Most patients were found to be homozygous for a specific haplotype in this population. Analysis of 24 tyrosinemia patients from 9 countries gave a frequency of approximately 52% for haplotype 6, suggesting a relatively high association worldwide.
Hahn et al. (1995) reviewed 7 previously reported mutations in tyrosinemia type I and added 2 more identified in compound heterozygous state.
Timmers and Grompe (1996) reported 6 new mutations in the FAH gene in patients with hereditary tyrosinemia type I: 2 splice mutations, 3 missense mutations, and 1 nonsense mutation.
Rootwelt et al. (1996) classified 62 hereditary tyrosinemia type I patients of various ethnic origins clinically into acute, chronic, or intermediate phenotypes and screened for the 14 published causal mutations in the FAH gene. Restriction analysis of PCR-amplified genomic DNA identified 74% of the mutated alleles. The IVS12+5G-A mutation (613871.0003), which is predominant in French Canadian tyrosinemia type I patients, was the most common mutation being present in 32 alleles in patients from Europe, Pakistan, Turkey, and the United States. The IVS6-1G-T mutation (613871.0010), encountered in 14 alleles, was common in central and western Europe. There was an apparent 'Scandinavian' 1009G-to-A combined splice and missense mutation (12 alleles), a 'Pakistani' 192G-to-T splice mutation (11 alleles), a 'Turkish' D233V mutation (6 alleles), and a 'Finnish' or northern European W262X (613871.0009) mutation (7 alleles). Rootwelt et al. (1996) commented that some of the mutations seemed to predispose for acute and others for more chronic forms of tyrosinemia type I, although no clear-cut genotype/phenotype correlation could be established.
Grompe et al. (1993) found that Fah -/- mice exhibited a phenotype significantly different from that of humans with null mutations in FAH. Fah -/- mice appeared normal at birth, but they rapidly developed hypoglycemia and liver dysfunction and died within 12 hours of birth. Fah -/- mice were not tyrosinemic. Electron microscopy revealed disruption of the endoplasmic reticulum in liver of Fah -/- mice.
Wuestefeld et al. (2013) noted that lethality in Fah -/- mice can be prevented by continuous treatment with the drug nitisinone (NTBC). Using short hairpin RNA screening, they found that stable knockdown of Mkk4 (601335) countered lethality in Fah -/- mice following NTBC withdrawal. Knockdown of Mkk4 robustly increased the regenerative capacity of hepatocytes and reduced the number of apoptotic hepatocytes in FAH -/- mice following NTBC withdrawal, as well as in mouse models of acute and chronic liver failure.
In a French Canadian patient with type I hereditary tyrosinemia (TYRSN1; 276700), Phaneuf et al. (1992) demonstrated compound heterozygosity for an FAH allele that appeared not to be expressed in the liver of the proband and a second allele that carried a 47A-T transversion which substituted isoleucine for asparagine-16 (N16I). These findings demonstrated that there are at least 2 different tyrosinemia mutations in the French Canadian population.
In a patient with type I hereditary tyrosinemia (TYRSN1; 276700) and very low FAH enzymatic activity in the liver, Labelle et al. (1993) found heterozygosity for an ala134-to-asp (A134D) mutation in the FAH gene. The nature of the other allele was not identified.
In a patient from eastern Quebec with tyrosinemia type I (TYRSN1; 276700), Grompe and Al-Dhalimy (1993) demonstrated homozygosity for a splice mutation consisting of a guanine-to-adenine alteration in the donor consensus sequence of intron 12 (IVS12+5G-A) of the FAH gene. Two other mutations, glu357-to-ter (E357X) and glu364-to-ter (E364X), were identified. Grompe et al. (1994) designed allele-specific oligonucleotide tests to detect the 3 mutations and used them to demonstrate that all patients with tyrosinemia type I in eastern Quebec carried the splice-donor site mutation, most of them in homozygous state. St-Louis et al. (1995) found the same mutation in a compound heterozygous Norwegian patient. The fact that this is the predominant mutation in French Canadian cases (having a frequency of 77.6% among Quebec patients with tyrosinemia type I) may indicate its ancient origin. The other mutation in the Norwegian patient was G337S (613871.0007).
The 2 extremes of the clinical phenotype of tyrosinemia type I are the 'acute' (a severe disorder with early onset and death), and 'chronic' (showing delayed onset and slow course) forms. Allelic heterogeneity and/or mutation reversion in hepatic cells had been proposed to explain the clinical heterogeneity. Poudrier et al. (1998) studied 2 probands from the French Canadian isolate where type I tyrosinemia is prevalent, one with the acute and the other with the chronic form. Both were found to be germline homozygotes for the IVS12+5G-A splice site mutation. Both showed liver mosaicism for FAH immunoreactivity with evidence for mutation reversion to heterozygosity in FAH-stained nodules as shown by amplification of DNA extracted from microdissected nodules. Western blot analysis of proteins from a reverted FAH-expressing nodule showed 29 +/- 3% FAH immunoreactive material as compared to an average normal liver. This was consistent with the measured FAH hydrolytic activity (25%) in this large regenerating nodule. These findings showed that genotypic heterogeneity is not a sufficient explanation for clinical heterogeneity and implicated epigenetic and other factors modifying the phenotype in this disorder.
Grompe and Al-Dhalimy (1993) found that a patient with tyrosinemia type I (TYRSN1; 276700) was compound heterozygous for 2 nonsense mutations in the FAH gene that changed the codon for glutamic acid at positions 357 and 364 of the enzyme to a stop codon (E357X and E364X, 613871.0005). One parent was from Quebec and the other from England.
For discussion of the glu364-to-ter (E364X) mutation in the FAH gene that was found in compound heterozygous state in a patient with tyrosinemia type I (TYRSN1; 276700) by Grompe and Al-Dhalimy (1993), see 613871.0004.
Rootwelt et al. (1994) found fumarylacetoacetase pseudodeficiency (see 276700) due to a C-to-T transition in nucleotide 1021 in the FAH gene, leading to an arg341-to-trp (R341W) substitution in 2.2% of FAH alleles among 516 healthy Norwegian volunteers.
St-Louis et al. (1995) found that a Norwegian patient with hepatorenal tyrosinemia (TYRSN1; 276700) was compound heterozygous for 2 mutations in the FAH gene; the IVS12+5G-A mutation (613871.0003), the most frequent mutation in French Canadian cases, and a glu337-to-ser (E337S) substitution.
In a French Canadian case of hereditary tyrosinemia type I (TYRSN1; 276700), St-Louis et al. (1995) found compound heterozygous mutations in the FAH gene: arg381-to-gly (R381G) inherited from the father, and glu357-to-ter (613871.0004) inherited from the mother.
St-Louis et al. (1994) reported a stop mutation in the FAH gene (W262X) in 5 Finnish patients with hereditary tyrosinemia type I (TYRSN1; 276700). This mutation seemed to predominate in the Finnish population, where it accounted for 95% of the alleles (19/20) in 10 affected patients tested (St-Louis et al. (1996)), and had not been found in any other population. The remaining allele carried the IVS12+5G-A splice site mutation (613871.0003) that is predominant in the French Canadian population but is also seen in patients of other origins. St-Louis et al. (1996) described a simple test for the 'Finnish' mutation.
In a study of 62 tyrosinemia type I (TYRSN1; 276700) patients of various ethnic origins, Rootwelt et al. (1996) found that the second most frequent FAH mutation was a G-to-T transversion in the last nucleotide of exon 6. Encountered in 14 alleles, the mutation was common in central and western Europe.
In a 37-year-old woman with type I tyrosinemia (TYRSN1; 276700) whose liver disease in infancy and rickets during childhood resolved with dietary therapy, Kim et al. (2000) reported an A-to-G transition in exon 9 of the FAH gene, resulting in a gln279-to-arg (Q279R) substitution, in compound heterozygosity with the IVS6-1G-T mutation (613871.0010). From 14 years of age the patient resumed an unrestricted diet with the continued presence of the biochemical features of tyrosinemia, yet maintained normal liver function. In adulthood she accumulated only small amounts of succinylacetone. Despite this evolution to a mild biochemical and clinical phenotype, she eventually developed hepatocellular carcinoma.
Berube, D., Phaneuf, D., Tanguay, R. M., Gagne, R. Assignment of the fumarylacetoacetate hydrolase gene to chromosome 15q23-15q25. (Abstract) Cytogenet. Cell Genet. 51: 962 only, 1989.
Demers, S. I., Phaneuf, D., Tanguay, R. M. Hereditary tyrosinemia type I: strong association with haplotype 6 in French Canadians permits simple carrier detection and prenatal diagnosis. Am. J. Hum. Genet. 55: 327-333, 1994. [PubMed: 7913582]
Grompe, M., Al-Dhalimy, M. Mutations of the fumarylacetoacetate hydrolase gene in four patients with tyrosinemia, type I. Hum. Mutat. 2: 85-93, 1993. [PubMed: 8318997] [Full Text: https://doi.org/10.1002/humu.1380020205]
Grompe, M., Al-Dhalimy, M., Finegold, M., Ou, C.-N., Burlingame, T., Kennaway, N. G., Soriano, P. Loss of fumarylacetoacetate hydrolase is responsible for the neonatal hepatic dysfunction phenotype of lethal albino mice. Genes Dev. 7: 2298-2307, 1993. [PubMed: 8253378] [Full Text: https://doi.org/10.1101/gad.7.12a.2298]
Grompe, M., St-Louis, M., Demers, S. I., Al-Dhalimy, M., Leclerc, B., Tanguay, R. M. A single mutation of the fumarylacetoacetate hydrolase gene in French Canadians with hereditary tyrosinemia type I. New. Eng. J. Med. 331: 353-357, 1994. [PubMed: 8028615] [Full Text: https://doi.org/10.1056/NEJM199408113310603]
Hahn, S. H., Krasnewich, D., Brantly, M., Kvittingen, E. A., Gahl, W. A. Heterozygosity for an exon 12 splicing mutation and a W234G missense mutation in an American child with chronic tyrosinemia type 1. Hum. Mutat. 6: 66-73, 1995. [PubMed: 7550234] [Full Text: https://doi.org/10.1002/humu.1380060113]
Jorquera, R., Tanguay, R. M. Fumarylacetoacetate, the metabolite accumulating in hereditary tyrosinemia, activates the ERK pathway and induces mitotic abnormalities and genomic instability. Hum. Molec. Genet. 10: 1741-1752, 2001. [PubMed: 11532983] [Full Text: https://doi.org/10.1093/hmg/10.17.1741]
Kim, S. Z., Kupke, K. G., Ierardi-Curto, L., Holme, E., Greter, J., Tanguay, R. M., Poudrier, J., D'Astous, M., Lettre, F., Hahn, S. H., Levy, H. L. Hepatocellular carcinoma despite long-term survival in chronic tyrosinaemia I. J. Inherit. Metab. Dis. 23: 791-804, 2000. [PubMed: 11196105] [Full Text: https://doi.org/10.1023/a:1026756501669]
Labelle, Y., Phaneuf, D., Leclerc, B., Tanguay, R. M. Characterization of the human fumarylacetoacetate hydrolase gene and identification of a missense mutation abolishing enzymatic activity. Hum. Molec. Genet. 2: 941-946, 1993. [PubMed: 8364576] [Full Text: https://doi.org/10.1093/hmg/2.7.941]
Phaneuf, D., Labelle, Y., Berube, D., Arden, K., Cavenee, W., Gagne, R., Tanguay, R. M. Cloning and expression of the cDNA encoding human fumarylacetoacetate hydrolase, the enzyme deficient in hereditary tyrosinemia: assignment of the gene to chromosome 15. Am. J. Hum. Genet. 48: 525-535, 1991. [PubMed: 1998338]
Phaneuf, D., Lambert, M., Laframboise, R., Mitchell, G., Lettre, F., Tanguay, R. M. Type 1 hereditary tyrosinemia: evidence for molecular heterogeneity and identification of a causal mutation in a French Canadian patient. J. Clin. Invest. 90: 1185-1192, 1992. [PubMed: 1401056] [Full Text: https://doi.org/10.1172/JCI115979]
Poudrier, J., Lettre, F., Scriver, C. R., Larochelle, J., Tanguay, R. M. Different clinical forms of hereditary tyrosinemia (type I) in patients with identical genotypes. Molec. Genet. Metab. 64: 119-125, 1998. [PubMed: 9705236] [Full Text: https://doi.org/10.1006/mgme.1998.2695]
Rootwelt, H., Brodtkorb, E., Kvittingen, E. A. Identification of a frequent pseudodeficiency mutation in the fumarylacetoacetase gene, with implications for diagnosis of tyrosinemia type I. Am. J. Hum. Genet. 55: 1122-1127, 1994. [PubMed: 7977370]
Rootwelt, H., Hoie, K., Berger, R., Kvittingen, E. A. Fumarylacetoacetase mutations in tyrosinaemia type I. Hum. Mutat. 7: 239-243, 1996. [PubMed: 8829657] [Full Text: https://doi.org/10.1002/(SICI)1098-1004(1996)7:3<239::AID-HUMU8>3.0.CO;2-5]
St-Louis, M., Leclerc, B., Laine, J., Salo, M. K., Holmberg, C., Tanguay, R. M. Identification of a stop mutation in five Finnish patients suffering from hereditary tyrosinemia type I. Hum. Molec. Genet. 3: 69-72, 1994. [PubMed: 8162054] [Full Text: https://doi.org/10.1093/hmg/3.1.69]
St-Louis, M., Poudrier, J., Phaneuf, D., Leclerc, B., Laframboise, R., Tanguay, R. M. Two novel mutations involved in hereditary tyrosinemia type I. Hum. Molec. Genet. 4: 319-320, 1995. [PubMed: 7757089] [Full Text: https://doi.org/10.1093/hmg/4.2.319]
St-Louis, M., Poudrier, J., Tanguay, R. M. Simple Detection of a (Finnish) hereditary tyrosinemia type 1 mutation. (Letter) Hum. Mutat. 7: 379-380, 1996. [PubMed: 8723698] [Full Text: https://doi.org/10.1002/(SICI)1098-1004(1996)7:4<379::AID-HUMU20>3.0.CO;2-Z]
Tanguay, R. M., Phaneuf, D., Labelle, Y., Demers, S. Molecular cloning and expression of the c-DNA encoding the enzyme deficient in hereditary tyrosinemia: evidence for molecular heterogeneity. (Abstract) Am. J. Hum. Genet. 47 (suppl.): A168 only, 1990.
Timmers, C., Grompe, M. Six novel mutations in the fumarylacetoacetate hydrolase gene of patients with hereditary tyrosinemia type I. Hum. Mutat. 7: 367-369, 1996. [PubMed: 8723690] [Full Text: https://doi.org/10.1002/(SICI)1098-1004(1996)7:4<367::AID-HUMU14>3.0.CO;2-0]
Wuestefeld, T., Pesic, M., Rudalska, R., Dauch, D., Longerich, T., Kang, T.-W., Yevsa, T., Heinzmann, F., Hoenicke, L., Hohmeyer, A., Potapova, A., Rittelmeier, I., and 11 others. A direct in vivo RNAi screen identifies MKK4 as a key regulator of liver regeneration. Cell 153: 389-401, 2013. [PubMed: 23582328] [Full Text: https://doi.org/10.1016/j.cell.2013.03.026]