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.
The FAH gene spans approximately 34 kb in the genomic DNA and has 14 coding exons. Mutations in this gene are the cause of tyrosinemia. About 40 different FAH mutations have been identified causing type I tyrosinemia. These mutations result in an unstable or inactive enzyme, which results in reduced or absent fumarylacetoacetate hydrolase activity. The most common mutation is a splice-site mutation (IVS12+5G>A) that results in disrupting the splicing mechanism that is essential for making the blueprint for producing fumarylacetoacetate hydrolase.
[See: Saudi Arabia > Imtiaz et al., 2011].
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.
Al-Shamsi et al. (2014) undertook a study to calculate the birth prevalence of IEMs among Emiratis in the UAE by taking into consideration all neonates born with an inherited metabolic condition at Tawam Hospital between 1995 and 2012. Type I Tyrosinemia was found to be one of the most prevalent IEMs identified in this study. Two different mutations were identified in the PAH gene among the affected patients; these included c.1156G>C (p.D386H), a novel mutation, and c.1A>G (p.M1V), a previously described mutation.