Catalase enzyme mutations and their association with diseases

Mol Diagn 2004; 8 (3): 141-149REVIEW ARTICLE 1084-8592/04/0003-0141/$31.00/0

© 2004 Adis Data Information BV. All rights reserved.

Catalase Enzyme Mutations and their Associationwith DiseasesLaszlo Goth,1,2 Peter Rass3 and Aniko Pay4

1 Department of Clinical Analytical Chemistry, Medical and Health Science Center, University of Debrecen,Debrecen, Hungary

2 Department of Clinical Biochemistry and Molecular Pathology, Medical and Health Science Center, University ofDebrecen, Debrecen, Hungary

3 Sigma-Aldrich Ltd, Budapest, Hungary4 Biological Research Center, Hungarian Academy of Science, Szeged, Hungary

Contents

Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1412. Catalase Enzyme . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1423. Catalase Gene and Protein . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1424. Benign Polymorphisms of Catalase Gene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1435. Association of Catalase Gene Mutations with Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143

5.1 Diabetes Mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1435.2 Blood Pressure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1445.3 Vitiligo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1445.4 Alzheimers Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1445.5 Decreased Catalase Activity in Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145

6. Acatalasemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1456.1 Clinical Features of Acatalasemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1456.2 Catalase Gene Mutations in Acatalasemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146

6.2.1 Japanese-Type Acatalasemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1466.2.2 Swiss-Type Acatalasemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1466.2.3 Hungarian-Type Acatalasemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146

6.3 Other Catalase Mutations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1477. Future Prospects for the Detection of Catalase Gene Mutations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147

Enzyme catalase seems to be the main regulator of hydrogen peroxide metabolism. Hydrogen peroxide atAbstracthigh concentrations is a toxic agent, while at low concentrations it appears to modulate some physiologicalprocesses such as signaling in cell proliferation, apoptosis, carbohydrate metabolism, and platelet activation.Benign catalase gene mutations of 5′ noncoding region (15) and intron 1 (4) have no effect on catalase activityand are not associated with disease.

Catalase gene mutations have been detected in association with diabetes mellitus, hypertension, and vitiligo.Decreases in catalase activity in patients with tumors is more likely to be due to decreased enzyme synthesisrather than to catalase mutations.

Acatalasemia, the inherited deficiency of catalase has been detected in 11 countries. Its clinical features mightbe oral gangrene, altered lipid, carbohydrate, homocysteine metabolism and the increased risk of diabetes

142 Goth et al.

mellitus. The Japanese, Swiss, and Hungarian types of acatalasemia display differences in biochemical andgenetic aspects. However, there are only limited reports on the syndrome causing these mutations.

These data show that acatalasemia may be a syndrome with clinical, biochemical, genetic characteristicsrather than just a simple enzyme deficiency.

Catalase is an enzyme which converts two molecules of hydro- Hydrogen peroxide appears to modulate the inflammatory processgen peroxide into two molecules of water and one of oxygen. This by regulating the expression of adhesive molecules, controllingheme-containing enzyme has been identified in the organs of cell proliferation, and apoptosis and modulating platelet aggrega-bacteria through to humans; in humans it is distributed in virtually tion.[25-31]

all aerobic tissue. A high concentration of hydrogen peroxide, due to a deficiencyDuring the first few decades of the last century the catalase (acquired or inherited) of catalase, especially when reacted with

enzyme was the subject of considerable biologic, chemical, redox-active metal ions such as iron or copper, yields the highlyclinical, and diagnostic research but its role remained obscure. In reactive hydroxyl radical in the Fenton and Haber-Weiss reaction.recent years further research has been undertaken into this ‘old’ This radical is responsible for injury in the cell membrane, mito-enzyme and this paper discusses these recently identified aspects chondrial electron transport, homocysteine metabolism, andof the catalase enzyme. DNA.[32-37]

Among the reactive oxygen species, hydrogen peroxide is2. Catalase Enzyme regarded as a key substrate in oxidative stress because this small,

diffusible molecule is stable under physiological conditions.Enzyme catalase (C 1.11.1.6) is the main regulator of hydrogen Toxic effects (damage of DNA, protein, cell membrane) due to

peroxide metabolism.[1,2] For the erythrocytes and other tissues, high concentrations of hydrogen peroxide can be decreased orsuch as the pancreas and heart, which have low catalase activi- abolished when extra catalase is added or generated.[18,32,38,39]

ty,[3-8] high concentrations of this enzyme in the erythrocytesprovides a defense against high concentrations of hydrogen perox- 3. Catalase Gene and Proteinide

Recently published papers on the tissue distribution of cata- The single locus coding for human catalase has been mapped tolase,[1,2,6] glutathione peroxidase,[9] and hemoglobin,[10,11] seem to 11p13. The catalase gene is 34 kb in length and contains 12confirm the predominant role that catalase has in the control of introns, 13 exons, and encodes for a protein of 526 aminohydrogen peroxide concentrations. acids.[40,41]

The enzymatic function of catalase has several unusual fea- Human catalase protein is a tetramer composed of four identicaltures: subunits, each contains a heme group. The subunits have four

• its reaction with hydrogen peroxide is first order and depends domains: (i) an extended non-globular amino terminal arm, whichentirely on the concentration of hydrogen peroxide; stabilizes the quaternary structure; (ii) an anti-parallel eight-

• at high substrate concentrations the rate of reaction is unusually stranded β barrel providing the residues on the distal side of therapid; heme; (iii) a rather random ‘wrapping domain’ around the subunit

• at low substrate concentrations, slow catalytic activity of the exterior including the proximal heme ligand; and (iv) a final α-two hydrogen peroxide substrates, and probably with the perox- helix structure.idatic activity with one hydrogen peroxide and one proton The pentacoordinated iron-heme is accessible at the distal sidedonor (ethanol), substrates play a role in the clearance of to peroxides at the bottom of the 25A long channel extending fromhydrogen peroxide.[4,11-13] the surface. This channel is critical for the molecular ruler recogni-These important catalase characteristics may help to explain the tion mechanism of hydrogen peroxide by the protein side-chains

increasing body of evidence which indicates a new role for hydro- histidine (His)75, asparagine (Asn)148, glutamine (Glu)168, andgen peroxide as a messenger of signaling.[13-22] aspartatic acid (Asp)128. The reactivity of heme iron is tuned by

Hydrogen peroxide is formed by pathways such as oxidase electron donation by the tryosine (Tyr)358 ligand and neutraliza-enzymes, reactive oxygen species,[23] and human tumor cells.[24] tion of the carboxylate charge by arginine (Arg)72, Arg112, Arg365,

© 2004 Adis Data Information BV. All rights reserved. Mol Diagn 2004; 8 (3)

Catalase Enzyme Mutations and their Association with Diseases 143

and the hydrogen bond involves Tyr358, Arg354, His258, and creased frequency of diabetes (12.7%) was found in HungarianAsp348.[42] acatalasemic families (table II).

The different catalase mutations in patients with diabetes4. Benign Polymorphisms of Catalase Gene

caused a decrease in blood catalase activities which may lead to

increased hydrogen peroxide concentrations in tissue and blood.The benign polymorphisms of the catalase gene are listed intable I. They include single nucleotide substitutions in flanking, 5′ These increased hydrogen peroxide levels may damage oxidation-noncoding, intron 1, and exons 1, 9, and 10. For these mutations, sensitive pancreatic β-cells leading to a decrease in insulin produc-no effect has been reported on catalase expression, decreased

tion.[33,61] The exact mechanisms by which hydrogen peroxidecatalase activity, or association with disease/pathologicalchanges.[43-46]

The HinfI restriction fragment length polymorphism (RFLP;Southern blot) of the 5′ noncoding and flanking region of thecatalase gene also showed the highly polymorphic characteristicsof these regions.[52]

In 2002 Casp et al.[53] reported on the association of a catalasegene silent mutation at position 111 in exon 9 (Asp384Asp) withvitiligo susceptibility. In case of a C to T polymorphism at –262 bpfrom the transcription site, the T variant showed a higher transcrip-tional activity in HepG2 and K562 cells.[48] A similar effect inhuman blood and liver cells can also be postulated. Further evi-dence from larger scale studies is required to prove an associationbetween human blood catalase activity and this polymorphism.

5. Association of Catalase Gene Mutationswith Disease

5.1 Diabetes Mellitus

An association between the catalase mutations and type 2diabetes mellitus has been investigated in a Moscow study.[47] 132healthy individuals and 154 patients with type 2 diabetes wereexamined for the polymorphic markers C1167T and two neighbor-ing mini-satellites (D1S5097 and D11S208). The genotype CC ofC1167T polymorphism was found to be associated with a higherrisk of type 2 diabetes. For the D1S5097 polymorphism, thefrequency of alleles 15 and 16 and genotype 18/20 were signifi-cantly higher in diabetic patients than in controls. For theD11S208 polymorphism, the frequency of alleles 17 and 18 andgenotype 18/20 were significantly higher in diabetic patients thanin controls. These data could suggest an association between thesethree catalase loci and type 2 diabetes.[47]

These polymorphisms were not associated with the develop-ment of diabetic nephropathy in patients with type 1 diabetes.[54]

The first report of an association between inherited catalasedeficiency and diabetes mellitus appeared in 2000.[33] An in-

Table I. Benign polymorphisms of the catalase gene

Mutation Position (numbering Region Referencein the original paper)

Mutation in noncoding regions

C to T –1167 Flanking 47

C to T –262 Flanking 48

G to A –259a (330) Flanking 49

A to T –21a Flanking 43

C to A –20 Flanking 45

C to T –18a Flanking 45

C to T 4a 5′ noncoding 46

A to G 17b (20) 5′ noncoding 53

T to C 20b 5′ noncoding 44

C to T 44b 5′ noncoding 46

T to C 49b 5′ noncoding 43

G to A –60c Intron 1 50

G to C 5 Intron 1 51

G to A 7 Intron 1 51

T to A 11 Intron 1 50

G to T 61 Intron 1 51

T to C 78 Intron 1 43

G to A 50 3′ noncoding 43

Mutations in coding regions

T to C 12 Exon 1 Ser3Ser 46

A to C 27 Exon 1 Ser27Arg 46

T to C 111 Exon 9 Asp389Asp 43

T to C 60 Exon 10 Leu418Leu 44

a Numbering corresponds to the number of basepairs as denoted byQuan et al.[41]

b Numbering corresponds to number of basepairs upstream from thetranscription site MET (ATG-initiating codon).

c Numbering corresponds to number of basepairs back from the firstnucleotide of exon 1. The C mutation at position 49 of 5′ uncodingregion was found to T to C by Goth[46] and this mutation wasdenoted to C to T earlier by Wen et al.[43]

Asn = asparagine; Asp = aspartatic acid; Arg = arginine; His = histidine;Leu = leucine; Met = methionine; Ser = serine; Tyr = tyrosine.


144 Goth et al.

Table II. Reported prevalence of inherited catalase deficiency and diabetes mellitus in Hungary

Activity (MU/L) Sex Diabetes Mutation References

nucleotide exon/intron codon

Acatalasemic

4.5 F Type 2 GA insertion e2 67 55


Hypocatalasemic


59.2 F Type 2 G insertion e2 48 57

30.9 F Type 2 G to A missense e9 354 58

50.8 F Type 2 G to Tt substitution i7 59

66.0 M Type 1 G to T substitution i7 59

60.3 F Type 2 T to A missense e2 53 60

58.9 F Type 2 G to C missense e2 66 60

Normocatalasemic (n = 33)

102.6 ± 18.4 F 13 No No 55-60M 20

effects pancreatic function/insulin production are still un- 5.3 Vitiligo

known.[33-35,38,39]

Vitiligo susceptibility is a complex genetic trait that may beThese data suggest that inherited catalase deficiency may be aassociated with the genes responsible for melanin biosynthesis,minor risk factor for diabetes mellitus, especially for type 2response to oxidative stress, and/or regulation of autoimmunity, asdiabetes. Beyond inherited catalase deficiency, other factors suchwell as environmental factors.as genetics and environmental effects are responsible for the

Both case-control and family-based genetic association studiesdevelopment of diabetes mellitus; 33 hypocatalasemic subjects inshowed that the T to C at position 20 of 5′ flanking region and T tothese families with the same mutation did not develop diabetesC at 60 of exon 10 (Leu418Leu) were not associated with vitili-mellitus.[33,50,61]

go.[53]

The T to C single nucleotide polymorphism (Asp389Asp) in5.2 Blood Pressure exon 9 suggests a possible association between this mutation and

vitiligo. The C allele is transmitted more frequently in patientswith vitiligo, which may contribute to the deficiency of catalaseThe first report to implicate the genetic variations of catalase inand accumulation of excess hydrogen peroxide.[53]

susceptibility to essential hypertension came from China inThis paper[53] revealed no data on catalase activity levels in2001.[49] Among the four single nucleotide polymorphisms (SNP;

blood while earlier studies[62] showed decreased catalase activitiesC to T at –773, G to A at –259, and T to A at –21 position ofin the epidermis of patients with vitiligo.flanking region, and A to G at +17 of 5′ noncoding region) only the

SNP at –773 demonstrated strong evidence (p < 0.002) of an

association with essential hypertension (systolic blood pressure 5.4 Alzheimers Disease

over 160mm Hg). This study included 37 individuals with hyper-

tension and 22 individuals (with a systolic blood pressure below The oxidative stress hypothesis is proposed as one of a number104mm Hg) as controls. The SNP at –773 in the promoter region of possible mechanisms underlying pathogenesis of Alzheimersof the catalase gene is predicted to both create and destroy tran- disease. This hypothesis it suggests that the accumulation ofscription factor binding sites, but it is not clear how they affect hydrogen peroxide in the brain of affected individuals may beblood pressure levels.[49] Furthermore, there are no data on catalase responsible for the development of the disease. Overproductionenzyme activities. and/or insufficient detoxification of hydrogen peroxide may trig-



ger a cascade of neurotoxic events contributing to the neural Switzerland, and Hungary have been characterized[76,89-91] usingdamage characteristic of the disease.[63] clinical, biochemical and molecular genetic methods, while the

identification of cases in other countries has been sporadic andIn a study of 137 controls and 137 patients with Alzheimersrelatively poorly characterized. The frequency of acatalasemia isdisease, the C to T nucleotide substitution at position –262 of the0.04 : 1000 in Switzerland, 0.8 : 1000 in Japan, and 0.05 : 1000 incatalase gene flanking region showed no difference in frequencyHungary; the frequency of hypocatalasemia is similar in Japan(p > 0.5). Therefore, this mutation does not confer a protective(2–4 : 1000) and in Hungary (2.3 : 1000).effect in respect to Alzheimers disease.[63]

5.5 Decreased Catalase Activity in Tumors 6.1 Clinical Features of Acatalasemia

Catalase activity in the liver has been known to be reduced[64,65]

In general, acatalasemia is a relatively benign syndrome.[77]

in a tumor size-dependent fashion and is restored to the normalOral gangrene and ulceration (Takahara disease) are associated

level by tumor removal.[66,67] These findings instigated extensivewith Japanese patients diagnosed with acatalasemia and appear in

research into a cancer toxin (toxohormone) that might be involvedroughly 20–50% of the cases, with a higher incidence in child-

in a cancer cachexia.[68,69] In 1973 Uenoyama and Ono[70] de-hood. It might be caused by catalase deficiency at the tissue level,

scribed two factors, one inhibitory and one stimulatory, which actdifferences in oral flora, lack of oral hygiene, and environmental

on catalase synthesis in rat liver. In tumors, the inhibitory factorfactors. Support for the latter is provided by the observation that its

had greater effect on the catalase synthesis than the stimulatoryfrequency declined in recent years.[91-93] Takahara disease has only

factor.been reported for patients with acatalasemia in Japan and Germa-

More recent studies showed that human tumor cells may pro-ny.[83,93] The ulceration and consequent gangrene are probably

duce large amounts of hydrogen peroxide[24] and that the decreasepromoted by hydrogen peroxide generated by phagocytic cells

in catalase activity is due to the depression of the catalase gene(neutrophils) and bacterial (streptococci, pneumococci) actions

transcription by an approximately 35 kDa nuclear protein bound toand the associated lack of catalase in the effected tissues and/or

the silencer element present in hepatoma cells but not in livererythrocytes.

cells.[71] There are data which suggest that catalase is also substan-Recent findings revealed increased cholesterol, low-density

tially modulated by signaling molecules.[72]

lipoprotein (LDL)-cholesterol, ApoB, Lp(a), and decreased LDLThese findings demonstrate that decreased catalase activity in

oxidative resistance in the Hungarian hypocatalasemic patientstumor cells, especially in the liver, is due to a regulatory mecha-

when these values were compared with those of normocatalasemicnism and not to catalase gene mutations, and similarly, the de-

family members. These changes may mean that these patients havecreased blood catalase activity in different tumors is due to the

a higher risk of coronary arterial diseases.[94]

decreased catalase synthesis.[73]

Furthermore, association of hyperhomocysteinemia and inher-ited catalase deficiency is associated with decreased folate and6. Acatalasemiaerythrocyte production.

The first human catalase deficiency was identified in Japanese After further investigation in the Hungarian acatalasemic andpatients in 1948.[74-76] Genetically, acatalasemia means the homo- hypocatalasemic patients, one of the acatalasemic patients died atzygous condition thus the term acatalasemia is actually a misno- the age of 60, she had had a mastectomy and hemicolectomy duemer as there is usually a small amount (<10%) of residual enzyme to breast carcinoma and residual tumor in the colon.[87] Her hypo-activity in erythrocytes, consequently hypocatalasemia may be a catalasemic brother died at the age of 77 due to prostate carcinomamore correct term. However, for the sake of convenience hypocat- (Goth, unpublished data). One hypocatalasemic female with type 2alasemia will indicate the heterozygous state with intermediate diabetes died at the age of 73 (Goth, unpublished data). For one(about 50%) levels of catalase activity.[77] hypocatalasemic male with type 1 diabetes, uncontrolled living

Acatalasemia is genetically a heterogenous condition with conditions and complications of his diabetes (uremia, hyperten-worldwide distribution. To date 113 cases of acatalasemia have sion, and subarachnoidal hemorrhage) are responsible for his earlybeen diagnosed in 59 families from 11 countries (Japan, Korea, death (aged 47; Goth, unpublished data). Another hypocatalasemicSwitzerland, Israel, US, Mexico, Germany, Peru, Iran, Austria, male died from a cerebrovascular lesion when he was 77 years oldand Hungary).[75,76,78-88] The patients with acatalasemia in Japan, (Goth, unpublished data). At autopsy, one acatalasemic and three


146 Goth et al.

hypocatalasemics had more atherosclerosis for their age than tion was detected in unrelated acatalasemics and 1 related hypo-normal (Goth, unpublished data). Contrary to these risk factors, catalasemic.[43,44]

the mean age for the living Hungarian acatalasemic/hypocat- The type B of Japanese acatalasemia was detected by Hirono etalasemic patients (45.1 ± 19.3y; n = 62) did not differ (p = 0.522) al.[57] in 1 homozygote and 4 heterozygotes in the same family.from that of normocatalasemic family members (42.9 ± 18.5y; n = This mutation showed a T deletion at 358 nucleotide position66) [Goth, unpublished data]. causing a frameshift mutation followed by a nonsense mutation.

New findings showed a higher incidence (12.7%) of diabetes in The truncated protein formed is unstable, with no catalase activity.Hungarian acatalasemic (2/2) and hypocatalasemic (6/61) pa-

6.2.2 Swiss-Type Acatalasemiatients.[33] One hypocatalasemic patient had type 1 diabetes (onsetat 7y) and two acatalasemic and 5 hypocatalasemic patients had There has been only a very limited study of Swiss-type catalasetype 2 diabetes (age of onset 43.0 ± 10.8y; range 35–56y). The mutations. This is most likely due to the early death of the programother hypocatalasemic patients (n = 55) and normocatalasemic coordinator (Dr H. Aebi). Crawford et al.[59] suggested that afamily members (n = 65) did not have diabetes. The manifestation regulatory mutation might be responsible for a truncated catalaseand diagnosis of symptomatic type 2 diabetes usually occur after protein. Earlier investigations[91] showed that this truncated prote-the age of 40;[95] two Hungarian hypocatalasemics experienced an in is less stable. This may explain why the catalase deficiency inearlier onset (35 and 36 years of age). the erythrocyte of long lifespan is more severe than in other cells

The increased frequency of diabetes, especially the non insulin- of short lifespan. This phenomena was not detected in either thedependent form, may be explained by the cumulative oxidative Japanese or Hungarian patients with acatalasemia.damage on pancreatic β-cells, especially on the mitochon-

6.2.3 Hungarian-Type Acatalasemiadria.[33-35,96,97]

Four novel catalase mutations have been reported for Hungari-Recent findings[33,36,94] show that acatalasemia is not only aan acatalasemic and hypocatalasemic patients. The detection ofbenign genetic polymorphism, but is also associated with changesthese mutations was based on a large scale catalase screeningin lipid, erythrocyte, and carbohydrate metabolism. There areprogram that involved 18 200 hospital/clinic patients and 4930reports of new techniques (from the polyethylene glycol conju-healthy individuals.[58,60,87]gates to catalase mimics and immuno-targeting) that can treat

inherited catalase deficiency.[55,56,98] • Hungarian Type A[99]: A GA insertion at nucleotide positionIt has been shown that artificial superoxide dismutase (SOD)/ 138 of exon 2 increased the GA repeat from 4 to 5. This

catalase mimics [Mn-Salem; manganase 3-methoxy N,N′-bis- insertion caused a frameshift in the amino acid sequence from(salycilidine)ethylenediamine chloride] can protect cells from oxi- 69 to 133 and generated a TGA termination codon at 134. Thisdative stress in a large number of disease models.[55] Similar truncated protein lacks the essential amino acid (His75) in thefavorable effects were found when the immuno-targeted delivery active center.[42] This mutation was detected in one acat-of catalase to the catalase poor endothelium was performed.[56] alasemic family (which included 2 acatalasemics and 6 hypo-

catalasemics) and in 3 hypocatalasmic families (totalling 236.2 Catalase Gene Mutations in Acatalasemia hypocatalasemics). We used a simple PCR-heteroduplex

screening method for the detection of this mutation.[100] TheSurprisingly, even with the early identification of the nucleo-

blood catalase activities of the acatalasemics were 4.5 MU/Ltide sequence of human catalase[40,41] and the large number of

(4.0%) and 7.6 MU/L (6.7%) and 49.2 ± 19.5 MU/L (45.8%; nacatalasemic families (n = 59), there are only a small number of

= 23) for the hypocatalasemics and were compared with thepublished papers on the catalase mutations responsible for de-

normocatalasemic (107.6 ± 19.5; n = 26) family members.creased catalase activity.

• Hungarian Type B[101]: This family had three hypocatalasemic6.2.1 Japanese-Type Acatalasemia (68.1 ± 5.91 MU/L, 52.2%) and four normocatalasemic (130.4Among the 46 acatalasemic families identified with the Japa- ± 8.7 MU/L) family members. The PCR-heteroduplex screen-

nese type of acatalasemia, only two syndrome causing mutations ing method yielded heteroduplex formation in exon 2. Thehave been reported.[43,44] A single G to A nucleotide substitution at nucleotide sequence analyzes revealed a G insertion at positionthe fifth position of intron 4 (splicing mutation) was responsible 79 in exon 2 causing a frameshift of amino acid sequence fromfor the catalase deficiency (Japanese type A). This splicing muta- 49 to 57 with a TGA stop codon at 58. This truncated protein



with its 58 amino acids instead of the 526 for the regular again because of its role as the main regulator of hydrogencatalase protein is not able to maintain the enzymatic function. peroxide metabolism.[1,2,5,6,8,10-12] Recent findings show that cata-

lase has a role in the regulation of hydrogen peroxide concentra-• Hungarian Type C[102]: The PCR single-strand conformationaltions in signaling.[13-22,25-31]polymorphism (SSCP) screening method demonstrated a muta-

tion in intron 7. The nucleotide sequence analyzes showed a G However, there are only limited papers on catalase mutationsto T substitution at position 5 of intron 7. The effect of this and their association with diseases such as diabetes mel-splice site mutation on the decreased catalase protein was litus,[33,54,61] hypertension,[49] and vitiligo[53] and only six syn-confirmed by Western blot analyzes. This mutation was de- drome causing mutations (two for Japanese and four for Hungari-tected in 7 hypocatalasemics (58.5 ± 11.5 MU/L, 60.6%) from an patients) have been identified.[43,44,50,57,99-102]

two hypocatalasemic families. The catalase activity of normo- Acatalasemia was thought to be a relatively benign enzymecatalasemic family members was 96.9 ± 4.1 MU/L (n = 7). deficiency,[77] but recent findings in Hungarian acatalasemic/hy-

• Hungarian Type D[50]: PCR-SSCP screening method showed a pocatalasemic patients revealed its association with diabetes[33,61]

mutation in exon 9. The G to A substitution at position 5 of and biochemical changes in lipid,[94] homocysteine, and erythro-exon 9 is a missense mutation changing Arg354 to histidine. The cyte metabolism.[36] Therefore, further studies are required toArg354, His218, Asp348 effect the promotion sites which stabi- examine catalase mutations in acatalasemia and diseases which arelize the electrostatic field generated by different iron oxidation associated with decreased catalase activity, such as diabetes, ath-states in the active center of catalase protein.[42] This mutation erosclerosis, or tumors.[73]

was found in 4 hypocatalasemics (55.6 ± 16.9 MU/L, 53.7%) of The regulatory role of catalase via hydrogen peroxide in signal-one hypocatalasemic family with 6 normocatalasemic (103.6 ± ing might be a new field of examination for catalase mutations.23.5 MU/L) family members. Any new findings on these fields will contribute to our understand-

ing of the different pathogenic mechanisms on molecular level.6.3 Other Catalase Mutations Furthermore, the detection of these mutations could be used in

clinical laboratory practice either in diagnosis or the estimation ofThree hundred and eight patients with type 2 diabetes were

risk factors of different diseases.examined for catalase gene mutations, two novel mutations weredetected.[51] The first was a T to A missense mutation at position

Acknowledgments96 of exon 2 causing the change of Asp53Glu. The second one is aG to C missense mutation at 135 nucleotide position of exon 2 This work was supported with grants of the Zsigmond Diabetes Founda-

tion (Hungarian Academy of Science, Budapest) and the Hungarian Scientificwhich causes the substitution of Glut66Cys (cysteine). TheseResearch Fund (OTKA T042985).amino acids are localized in the neighboring region of valine

The authors have provided no information on sources of funding or on(Val)44, Arg72, Val73, Val74, and His75 which are important in theconflicts of interest directly relevant to the content of this review.

heme-protein interaction[42] and could cause decreased (58.7% and48.2%) catalase enzyme activities. These mutations have been

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Catalase enzyme mutations and their association with diseases