Fumarylacetoacetate Hydrolase

Alternative Names

  • FAH
  • Fumarylacetoacetase

Associated Diseases

Tyrosinemia, Type I
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OMIM Number

613871

NCBI Gene ID

2184

Uniprot ID

P16930

Length

34,460 bases

No. of Exons

15

No. of isoforms

2

Protein Name

Fumarylacetoacetase

Molecular Mass

46374 Da

Amino Acid Count

419

Genomic Location

chr15:80,152,788-80,186,948

Gene Map Locus
15q25.1

Description

The Fumarylacetoacetate Hydrolase (FAH) gene is located on chromosome 15q25.1. It encodes a protein of 419 amino acids, and weighs about 46 kDa. Fumarylacetoacetate hydrolase is the last enzyme in the tyrosine catabolism pathway. It converts a tyrosine byproduct called fumarylacetoacetate into smaller molecules that are either excreted by the kidneys or used in reactions that produce energy. Fumarylacetoacetate hydrolase is found in large amounts in the liver and kidneys, and smaller amounts are found in many tissues throughout the body.

Defects of the fumarylacetoacetate hydrolase enzyme are the cause of tyrosinemia; a metabolic disease characterized by elevations of tyrosine in the blood and urine, and hepatorenal manifestations. Some of the most common symptoms of this disease include hepatic necrosis, renal tubular injury, episodic weakness, self-mutilation, and seizures.

Epidemiology in the Arab World

View Map
Variant NameCountryGenomic LocationClinvar Clinical SignificanceCTGA Clinical Significance Condition(s)HGVS ExpressionsdbSNPClinvar
NM_000137.4:c.1A>GSaudi Arabia; United A...NC_000015.10:g.80153055A>GPathogenicPathogenicTyrosinemia, Type ING_012833.1:g.5057A>G; NM_000137.4:c.1A>G; NP_000128.1:p.Met1Val1057517972372766
NM_001374377.1:c.1001C>TSaudi Arabiachr15:80180164PathogenicTyrosinemia, Type ING_012833.1:g.32166C>T; NM_001374377.1:c.1001C>T; NP_001361306.1:p.Ser334Phe762404387
NM_001374377.1:c.1022G>CEgyptchr15:80180185PathogenicPathogenicTyrosinemia, Type ING_012833.1:g.32187G>C; NM_001374377.1:c.1022G>C; NP_001361306.1:p.Arg341Pro903038605598073
NM_001374377.1:c.1027G>CEgyptchr15:80180190PathogenicPathogenicTyrosinemia, Type ING_012833.1:g.32192G>C; NM_001374377.1:c.1027G>C; NP_001361306.1:p.Gly343Arg970505762558592
NM_001374377.1:c.1156G>CUnited Arab EmiratesNC_000015.10:g.80181135G>CUncertain SignificanceLikely PathogenicTyrosinemia, Type ING_012833.1:g.33137G>C; NM_001374377.1:c.1156G>C; NP_001361306.1:p.Asp386His1555442402552656
NM_001374377.1:c.1190delEgyptchr15:80186139PathogenicPathogenicTyrosinemia, Type ING_012833.1:g.38141del; NM_001374377.1:c.1190del; NP_001361306.1:p.Gln397fs786204551188907
NM_001374377.1:c.1195G>CSaudi Arabiachr15:80186144PathogenicPathogenicTyrosinemia, Type ING_012833.1:g.38146G>C; NM_001374377.1:c.1195G>C; NP_001361306.1:p.Asp399His1449927772553045
NM_001374377.1:c.364+1G>AEgypt; Saudi Arabiachr15:80160460PathogenicTyrosinemia, Type ING_012833.1:g.12462G>A; NM_001374377.1:c.364+1G>A866205298
NM_001374377.1:c.374C>GEgyptchr15:80162255PathogenicTyrosinemia, Type ING_012833.1:g.14257C>G; NM_001374377.1:c.374C>G; NP_001361306.1:p.Thr125Arg777702711
NM_001374377.1:c.509G>TSaudi Arabiachr15:80168105PathogenicTyrosinemia, Type ING_012833.1:g.20107G>T; NM_001374377.1:c.509G>T; NP_001361306.1:p.Gly170Val747300179
NM_001374377.1:c.607-1G>AEgypt; Saudi Arabiachr15:80172148PathogenicPathogenicTyrosinemia, Type ING_012833.1:g.24150G>A; NM_001374377.1:c.607-1G>A771712041188755
NM_001374377.1:c.680G>CEgyptchr15:80172222PathogenicPathogenicTyrosinemia, Type ING_012833.1:g.24224G>C; NM_001374377.1:c.680G>C; NP_001361306.1:p.Gly227Ala
NM_001374377.1:c.709C>TSaudi Arabiachr15:80173016PathogenicPathogenicTyrosinemia, Type ING_012833.1:g.25018C>T; NM_001374377.1:c.709C>T; NP_001361306.1:p.Arg237Ter769550316437463
NM_001374377.1:c.782C>TEgypt; Saudi Arabiachr15:80173089PathogenicPathogenicTyrosinemia, Type ING_012833.1:g.25091C>T; NM_001374377.1:c.782C>T; NP_001361306.1:p.Pro261Leu8033889821058
NM_001374377.1:c.787G>ASaudi Arabiachr15:80173094PathogenicPathogenicTyrosinemia, Type ING_012833.1:g.25096G>A; NM_001374377.1:c.787G>A; NP_001361306.1:p.Val263Met1168279912553987

Other Reports

Egypt

Imtiaz et al (2011) investigated mutations in the FAH gene among 43 patients affected with Hereditary Tyrosinemia Type 1. The patients included Saudi Arabians and Egyptians. Sequencing of the FAH gene using intronic primers from the patients identified 16 different mutations in the Arab patients, 10 of which were novel mutations. These new mutations include eight missense mutations (p.125Thr>Arg, p.170Gly>Val, p.227 Gly>Ala, p.263Val>Met, p.334Ser>Phe, p.341Arg>Pro, p.343Gly>Arg, and p.400Asp>His), one splice site mutation (IVS4+1G>A), and a single nucleotide deletion (c.11.90delA). The last mutation causes a frameshift and is expect to result in an abnormally long protein. These novel mutations were not found in a sample of 200 healthy controls. All the parents whose DNA was analyzed were found to be heterozygous carriers of these mutations. Polyphen and Mutation Taster softwares predicted all of these new mutations to be probably damaging or disease causing. In a further seven patients, exon sequencing was unable to identify any mutations in the FAH gene.

Saudi Arabia

Imtiaz et al (2011) investigated mutations in the FAH gene among 43 patients affected with Hereditary Tyrosinemia Type 1. The patients included Saudi Arabians and Egyptians. Sequencing of the FAH gene using intronic primers from the patients identified 16 different mutations in the Arab patients, 10 of which were novel mutations. These new mutations include eight missense mutations (p.125Thr>Arg, p.170Gly>Val, p.227 Gly>Ala, p.263Val>Met, p.334Ser>Phe, p.341Arg>Pro, p.343Gly>Arg, and p.400Asp>His), one splice site mutation (IVS4+1G>A), and a single nucleotide deletion (c.11.90delA). The last mutation causes a frameshift and is expect to result in an abnormally long protein. These novel mutations were not found in a sample of 200 healthy controls. All the parents whose DNA was analyzed were found to be heterozygous carriers of these mutations. Polyphen and Mutation Taster softwares predicted all of these new mutations to be probably damaging or disease causing. In a further seven patients, exon sequencing was unable to identify any mutations in the FAH gene.

Mohamed et al. (2013) reported two Saudi siblings with tyrosinemia type 1. Case 1 was a male infant who presented at two months of age with fever, vomiting and refusal of feeding. An FAH gene study identified a c.1 A?>?G homozygous mutation. Case 2 was the younger brother of Case 1, and was born 6 months after his brother had been confirmed with tyrosinemia. DNA analysis identified the same homozygous mutation, as in his brother.

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