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

Abstract

BackgroundTyrosinemia 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.MethodsSequencing of FAH and their exon–intron boundaries and in silico protein modeling based on the crystallographic structure of mouse FAH.ResultsWe 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.ConclusionHT1 patients had a heterogeneous mutational and clinical spectrum and no genotype–phenotype correlation could be established.

The compound heterozygous mutations of c.607G>a and c.657delC in the FAH gene are associated with renal damage with hereditary tyrosinemia type 1 (HT1)

“…To date, over 900 mutations of FAH have been identified. Among them, around 100 variants were reported to be associated with HT1 (Table S1) (Angileri et al, 2015; Angileri, Bergeron, et al, 2014; Angileri, Morrow, et al, 2014; Awata et al, 1994; Baydakova et al, 2019; Bergman et al, 1998; Couce et al, 2011; Dursun et al, 2011; Forget et al, 1999; Gokay et al, 2016; Ibarra‐González et al, 2019; Imtiaz et al, 2011; Introne, 2021; Kawabata et al, 2022; Luijerink et al, 2004; Maiorana et al, 2014; McKiernan et al, 2015; Morrow et al, 2017; Morrow et al, 2019; Nakamura et al, 2007; Pérez‐Carro et al, 2014; Ploos van Amstel et al, 1996; Van Dyk et al, 2010; van Spronsen et al, 1994; Wu & Hurst, 2016). It was worth noting that the most frequent FAH mutation to cause HT1 is c.1062+5G>A (IVS12+5G>A) (32.3%), followed by c.554‐1G>T (IVS6‐1G>T) (16.4%) and c.786G>A (p.W262X) (5.6%) (Angileri, Bergeron, et al, 2014).…”

“…Insights on the relationship between gene polymorphisms and amino acid metabolism have helped target FAH mutation‐mediated tyrosinemia processes underlying renal dysfunction (Angileri, Bergeron, et al, 2014; Dursun et al, 2011; Morrow et al, 2017). Up to now, approximately 100 pathogenic FAH variants have been reportedly associated with HT1, and despite numerous studies, no clear genotype–phenotype map has been established (Angileri, Bergeron, et al, 2014; Baydakova et al, 2019; Ibarra‐González et al, 2019). For children with atypical clinical manifestations, the identification of biallelic pathogenic FAH variants using molecular genetic testing should be combined, especially for prenatal diagnoses.…”

“…numerous studies, no clear genotype-phenotype map has been established (Angileri, Bergeron, et al, 2014;Baydakova et al, 2019;Ibarra-González et al, 2019). For children with atypical clinical manifestations, the identification of biallelic pathogenic FAH variants using molecular genetic testing should be combined, especially for prenatal diagnoses.…”

A Review of Disparities and Unmet Newborn Screening Needs over 33 Years in a Cohort of Mexican Patients with Inborn Errors of Intermediary Metabolism

“…At our institution, Sanger sequencing is the only methodology available for genotyping [ 75 ]. This is the main reason why we have only performed the genetic studies of six groups of conditions (HPA/PKU [ 27 ], TYR-1 [ 76 ], GALAC [ 20 ], tetrahydrobiopterin defects (BH 4 D) [ 28 ], cystinosis (CTNS) [ 22 ], and MMA [ 21 ]) at our center and only under research protocols, not as permanently available routine tests ( Table S2 ); thus, molecular studies of the patients were not always performed at the same time of their arrival to our institution. Technological modernization and investment in adequate genotyping methods are needed to fill this gap.…”

Identification and functional characterization of a novel homozygous intronic variant in the fumarylacetoacetate hydrolase gene in a Chinese patient with tyrosinemia type 1

“…HT1 can lead to severe liver and renal dysfunction [ 14 ]. Clinical and biochemical findings of the patient indicated that she suffered from HT1, which was caused by variants of FAH gene.…”