Article

Impaired DNA repair and genomic stability in hereditary tyrosinemia type 1.

Centre for Human Metabonomics, School for Physical and Chemical Sciences, North-West University, Potchefstroom, 2520, South Africa.
Gene (impact factor: 2.34). 12/2011; 495(1):56-61. DOI:10.1016/j.gene.2011.12.021 pp.56-61
Source: PubMed

ABSTRACT The autosomal recessive disorder, hereditary tyrosinemia type 1 (HT1), is caused by a defective fumarylacetoacetate hydrolase enzyme. Consequently intermediate metabolites such as fumarylacetoacetate, succinylacetone and p-hydroxyphenylpyruvic acid accumulate. Characteristic to HT1 is the development of hepatocellular carcinoma, irrespective of dietary intervention or pharmacological treatment. Carcinogenesis may occur through a chromosomal instability mutator phenotype or a microsatellite instability phenotype, and deficient DNA repair may be a contributing factor thereof. The purpose of this study was to investigate the expression of DNA repair proteins, and the possible occurrence of microsatellite instability in HT1. Gene expression analyses show low expression of hOGG1 and ERCC1 in HT1 patient lymphocytes. Results from microsatellite instability analyses show allelic imbalance on chromosome 7 of the fah(-/-) mouse genome, and instability of the D2S123, D5S346 and (possibly) D17S250 microsatellite markers, in HT1 patient lymphocytes.

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Keywords

allelic imbalance
 
autosomal recessive disorder
 
chromosomal instability mutator phenotype
 
chromosome 7
 
contributing factor
 
defective fumarylacetoacetate hydrolase enzyme
 
dietary intervention
 
ERCC1
 
hepatocellular carcinoma
 
hereditary tyrosinemia type 1
 
hOGG1
 
HT1 patient lymphocytes
 
instability
 
microsatellite instability
 
microsatellite instability analyses
 
microsatellite instability phenotype
 
p-hydroxyphenylpyruvic acid
 
pharmacological treatment
 
possible occurrence
 
proteins