Mutational spectrum of Mexican patients with tyrosinemia type 1: In silico modeling and predicted pathogenic effect of a novel missense FAH variant

Background Tyrosinemia type 1 (HT1, MIM#276700) is caused by a deficiency in fumarylacetoacetate hydrolase (FAH) and it is associated with severe liver and renal disfunction. At present, the mutational FAH (15q25.1, MIM*613871) spectrum underlying HT1 in the Mexican population is unknown. The objective of this study was to determine the FAH genotypes in eight nonrelated Mexican patients with HT1, who were diagnosed clinically. Methods Sequencing of FAH and their exon–intron boundaries and in silico protein modeling based on the crystallographic structure of mouse FAH. Results We identified pathogenic variants in 15/16 studied alleles (93.8%). Nine different variants were found. The most commonly detected HT1‐causing allele was NM_000137.2(FAH):c.3G > A or p.(?) [rs766882348] (25%, n = 4/16). We also identified a novel missense variant NM_000137.2(FAH):c.36C > A or p.(Phe12Leu) in a homozygous patient with an early and fatal acute form. The latter was classified as a likely pathogenic variant and in silico protein modeling showed that Phe‐12 residue substitution for Leu, produces a repulsion in all possible Leu rotamers, which in turn would lead to a destabilization of the protein structure and possible loss‐of‐function. Conclusion HT1 patients had a heterogeneous mutational and clinical spectrum and no genotype–phenotype correlation could be established. A heterogeneous clinical and mutational spectrum of FAH was found in Mexican patients with tyrosinemia type 1 and a novel missense variant c.36C > A or p.(Phe12Leu) associated with the fatal acute form of the disease was described. This variant based on protein modeling, would cause a destabilization of FAH structure.