Gene expression profiling of Fah- and Hgd-deficient mouse livers upon short-term nitisinone discontinuation

Dataset

Description

FAH5981SB mice (C57Bl/6J background) bear a mutation that is a G-to-A transition at the last base of VEGA exon OTTMUSE00000329891 leading to the splicing out of this exon, which results in a frameshift and subsequently the introduction of a premature stop codon at amino acid position 303, ultimately leading to formation of truncated, unstable and degraded Fah protein and served thereby as experimental model for HT1. The homozygous Hgd knockout-first allele mouse (Hgd tm1a-/-) (C57Bl/6J background), is an animal model of human AKU. Hgd tm1a-/- mice contain an IRES:LacZ gene trap cassette and a promoter-driven neo cassette inserted into the fifth Hgd intron with the sixth exon flanked by loxP sequences. Homozygous Hgd tm1a-/- mice therefore show an AKU phenotype based on Hgd gene disruption. Hgd tm1a-/- mice develop specific symptoms of AKU including blackening of urine and progressive osteoarthritis when NTBC is not administered. Fah- and Hgd-deficient mice were either continuously treated with 8 mg/L NTBC through their drinking water or deprived from NTBC therapy for seven consecutive days. Withdrawal samples were collected seven days after NTBC discontinuation.

Abstract

Hereditary tyrosinemia type 1 (HT1) is a severe genetic disorder that affects the liver due to a defective fumarylacetoacetate hydrolase (Fah) enzyme in hepatocytes. The drug nitisinone (NTBC) has offered a life-saving treatment for HT1 patients by inhibiting the upstream enzyme 4-hydroxyphenylpyruvate dioxygenase (HPD).
We used microarray analyses to to identify changes in molecular pathways associated to the development and progression of the liver pathogenesis of HT1 that remain uncorrected under NTBC therapy by using gene expression profiling of Fah-deficient mouse livers subjected to continuous NTBC therapy and after seven days of NTBC therapy discontinuation. As a control of a TIMD without hepatic manifestation, we used the Hgd-deficient mouse model of AKU, also under continuous NTBC treatment and after seven days of NTBC therapy discontinuation. Consequently, we identified a set of 25 genes that discriminates HT1 livers from AKU livers, even under continuous NTBC therapy, as such representing remnants of an HT1-driven residual uncorrected liver disease phenotype.
Datum van beschikbaarheid4 apr 2023
UitgeverNCBI Gene Expression Omnibus
Tijdelijke dekking2022 - 2023
Datum van data-aanmaak4 apr 2023
Geografische dekkingJette

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