Detection of a novel familial catalase mutation (Hungarian type D) and the possible risk of inherited catalase deficiency for diabetes mellitus

Abstract

The enzyme catalase is the main regulator of hydrogen peroxide metabolism. Recent findings suggest that a low concentration of hydrogen peroxide may act as a messenger in some signalling pathways whereas high concentrations are toxic for many cells and cell components. Acatalasemia is a genetically heterogeneous condition with a worldwide distribution. Yet only two Japanese and three Hungarian syndrome-causing mutations have been reported. A large-scale (23 130 subjects) catalase screening program in Hungary yielded 12 hypocatalasemic families. The V family with four hypocatalasemics (60.6 +/- 7.6 MU/L) and six normocatalasemic (103.6 +/- 23.5 MU/L) members was examined to define the mutation causing the syndrome. Mutation screening yielded four novel polymorphisms. Of these, three intron sequence variations, namely G-->A at the nucleotide 60 position in intron 1, T-->A at position 11 in intron 2, and G-->T at position 31 in intron 12, are unlikely to be responsible for the decreased blood catalase activity. However, the novel G-->A mutation in exon 9 changes the essential amino acid Arg 354 to Cys 354 and may indeed be responsible for the decreased catalase activity. This inherited catalase deficiency, by inducing an increased hydrogen peroxide steady-state concentration in vivo, may be involved in the early manifestation of type 2 diabetes mellitus for the 35-year old proband.

Sensitization to alloxan-induced diabetes and pancreatic cell apoptosis in acatalasemic mice

“…Similar results with catalase gene mutations and type 2 diabetes were reported in humans, and this risk might be due to peroxide damage of normally catalase-poor pancreatic β cells [30]. Goth reported a proband of type D Hungarian acatalasemia develop type 2 diabetes at a relatively early age [31] and there is higher incidence of diabetes (type 1 and 2) in a catalase deficient family than a normocatalasemic family [5]. The acatalasemic diabetes mice model may reveal the exact mechanisms by which hydroxyl radical affects pancreatic dysfunction and it may lead to the development of new treatments for human diabetes.…”

The peroxisome: an update on mysteries

“…In summary, there is growing evidence that mitochondria and peroxisomes possess an interconnected redox-homeostasis system, which is regulated by yet unknown signaling events. Amazingly, acatalasemia is generally reported as a benign disorder; however, Goth et al (2005) reported an increased incidence of diabetes mellitus in a Hungarian family hypothesizing that an increased ROS production could damage the insulin-producing b-cells of the pancreas. The significance of this assumption has very recently been affirmed in a study which demonstrated that diabetesassociated lipotoxicity was caused by H 2 O 2 -production during peroxisomal b-oxidation, since pancreatic b-cells showed very low levels of catalase expression , thus interconnecting peroxisomal ROS with another age-related disease.…”

Polymorphisms of antioxidant enzymes, blood pressure and risk of hypertension

“…Catalase is also an important enzyme in the reactions to reduce superoxide levels, and thereby prevents cell damage [41]. Patients with reduced catalase activity have a higher incidence of oxidative stress-related diseases such as atherosclerosis [42], diabetes [43,44] and dyslipidemia [45]. The last gene in which an association has been found is the thioredoxin gene.…”