Identification of the Mutations Spectrum in the Fumarylacetoacetate Hydrolase Gene in Tyrosinemia Type 1 Patients in Northeastern Iran.

Tyrosinemia type 1 is a rare disease with autosomal recessive inheritance. It occurs as a result of mutations in fumarylacetoacetate hydrolase (FAH), causing the accumulation of succinylacetone (SA) and fumarylacetoacetate metabolites, leading to severe damage to the patient's liver and kidney. The present study aimed to identify FAH mutations in patients with tyrosinemia type 1 from northeastern Iran. This research was a cross-sectional study to determine the spectrum of mutations in 14 patients with tyrosinemia type 1 in northeastern Iran. Blood and urine samples were collected from the patients to measure the plasma levels of amino acids (tyrosine, methionine, and phenylalanine) and the urine levels of SA using high-performance liquid chromatography (HPLC) and gas chromatography-mass spectrometry (GC-MS) techniques, respectively. DNA was extracted from the whole blood samples, and then the FAH gene segment was amplified using the polymerase chain reaction (PCR) technique. The PCR products were subsequently sequenced using the Sanger method. In patients' blood, the mean phenylalanine concentration was 49 ± 15.5 µmol/L (reference: 32-85 µmol/L), and methionine was 23.8 ± 2.5 µmol/L (reference: 12-40 µmol/L). The mean tyrosine concentration was 491 ± 153 µmol/L (reference: 10-145 µmol/L). Urine succinylacetone concentration was 131 ± 3.5 mmol/L, nearly 400 times higher than the reference upper limit (0.3 mmol/L). In this study, a total of 11 variants were identified in the FAH gene; including three new ones (c.618A > G, c.1068A > T, and c.331G > A), and eight previously reported variations (c.82-13G > A, c.1062 + 5G > A, c.1009G > A, c.364 + 1G > A, c.961-15G > A, c.709C > T, c.782C > T, and c.267G > C). This study led to the identification of 11 variants in the FAH gene including three novel variants in the patients with tyrosinemia type 1 in Northeastern Iran. These findings can be applied to study the potential role of these mutations in the disease pathogenesis, as well as their potential use in its diagnosis.