Molecular Aspects of the FAH Mutations Involved in HT1 Disease

Abstract

Hereditary tyrosinemia type 1 (HT1) is caused by the lack of fumarylacetoacetate hydrolase (FAH), the last enzyme of the tyrosine catabolic pathway. Up to now, around 100 mutations in the FAH gene have been associated with HT1, and despite many efforts, no clear correlation between genotype and clinical phenotype has been reported. At first, it seems that any mutation in the gene results in HT1. However, placing these mutations in their molecular context allows a better understanding of their possible effects. This chapter presents a closer look at the FAH gene and its corresponding protein in addition to provide a complete record of all the reported mutations causing HT1.

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

“…Here, we documented seven different genotypes, with a predominance of homozygosity (5/8, 62.5%, Table 1), which is similar to that reported in Spain 66% (Moreno‐Estrada et al, ) and Turkey 60% (Couce et al, ). The highly heterogeneous mutational spectrum identified in this study is consistent with that reported worldwide (Angileri et al, ; Couce et al, ; Morrow et al, ). We found that one‐third (3/9) of the pathogenic FAH alleles were in exon 1, which differ from that reported by other authors, who describe exons 9 and 12 as harboring the largest clusters of disease‐causing FAH variants (Morrow et al, ).…”

“…Despite the fact that no clear correlation between genotype and phenotype has been established for HT1, analyses of the protein structure of pathogenic FAH alleles could facilitate a better understanding of their potential clinical effects (Morrow et al, ). Furthermore, establishing the causative FAH genotype would be useful for accurate genetic counseling (Mayorandan et al, ) and prenatal diagnosis in families that require it.…”

Multiplex precise base editing in cynomolgus monkeys

“…First, we tested whether targeted base editing works in cynomolgus monkey embryos using BE3, a cytosine base editor (CBE) consisting of the Cas9 nickase fused to rAPOBEC1 and a uracil glycosylase inhibitor 5 . We chose the gene fumarylacetoacetate hydrolase (FAH), in which mutations cause tyrosinemia 16 , as an initial target for our studies. Currently,~100 mutations have been found in hereditary tyrosinemia type 1 (HT1) patients 16 .…”

Clinical Features of 29 Patients with Hereditary Tyrosinemia I in Western Turkey

“…In this manner, the treatment to be started before the development of clinical symptoms improves the prognosis of disease (10,11). Mutation analysis of FAH gene provides confirmation of the diagnosis and antenatal diagnosis (12). The phenylalanine and tyrosine restricted diet and nitisinone NTBC are base in the treatment of HTI.…”

“…The FAH gene is mapped in human chromosome 15q (15q23-25) and consists of 14 exons spanning over 35 kb of DNA. Up to now, approximately 100 mutations in the FAH gene have been associated with HTI and the mutations are listed in the Human Genome Mutation database (HGMD ® Professional 2016.1, accessed on April 2016) (3,4).…”