Elsevier

Clinical Biochemistry

Volume 40, Issue 15, October 2007, Pages 1100-1103
Clinical Biochemistry

Oxidative stress biomarkers in four Bloom syndrome (BS) patients and in their parents suggest in vivo redox abnormalities in BS phenotype

https://doi.org/10.1016/j.clinbiochem.2007.06.003Get rights and content

Abstract

Objective:

To evaluate an association of Bloom syndrome (BS) phenotype with an in vivo prooxidant state.

Methods:

The following endpoints were measured in 4 BS patients, their 6 parents, and 78 controls: a) leukocyte and urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG); b) blood glutathione (GSSG and GSH), c) plasma levels of some plasma antioxidants (uric acid, UA, ascorbic acid, AA, α- and γ-tocopherol), and of glyoxal (Glx) and methylglyoxal (MGlx).

Results:

Leukocyte 8-OHdG levels were significantly increased in the 4 BS patients vs. 40 controls (p = 0.04), while the urinary 8-OHdG levels were non-significantly increased in BS patients. Glutathione disulfide levels and GSSG/GSH ratio were significantly decreased in BS patients vs. 44 controls (p = 0.02). The plasma levels of UA in BS patients were significantly increased vs. 24 controls (p = 0.005). No significant alterations were found in the in the plasma levels of Glx, MGlx, AA, and tocopherol. No changes in the tested parameters were found in the BS heterozygotes.

Conclusion:

This report shows a significant increase in oxidative DNA damage in leukocytes and in plasma UA levels from 4 BS patients. Should these data be confirmed in more extensive BS patient groups, an involvement of oxidative stress in the clinical BS phenotype might be suggested.

Introduction

Bloom syndrome (BS, OMIM #210900) is a very rare autosomal recessive disorder, caused by mutations in the BLM gene encoding the DNA helicase RecQ protein-like-3 and located to 15q26.1 [1], [2]. The clinical BS phenotype is characterized by hypersensitivity to sunlight with facial telangiectasia in butterfly midface pattern, severe growth retardation, immunodeficiency, and very high frequency of malignancies of several cell types and sites [3], [4]. The cytogenetic analysis of BS cells shows multiple non-specific chromosomal breakages with interchanges (mostly between homologous chromosomes), and a marked increase in sister chromatid exchanges (SCE) [5], [6], [7]. The current opinion on BS attributes the disease to defective DNA repair as the BLM protein belongs to the RecQ family of helicases, and has similarity to the Werner syndrome protein (WRN) and to the product of the yeast gene SGS1, suggesting that the proteins play similar roles in metabolism, namely by interacting with topoisomerases [8], [9], [10].

Another line of studies suggested that the BS phenotype might be related to oxidative stress based on redox abnormalities in cultured cells from BS patients [11], [12], [13], [14], [15], [16]. However, to date no report is available, to the best our knowledge, evaluating any in vivo abnormalities in oxidative stress biomarkers in BS patients or BS heterozygotes. The present investigation, as a part of a more extensive study of oxidative stress in some cancer-prone genetic diseases [17], [18], [19], was conducted on four BS patients (two siblings and two unrelated patients) and their six parents (obligate heterozygotes), in the hypothesis that an in vivo prooxidant state may be associated to the BS phenotype.

Section snippets

Study population

Four patients with BS, one male and three females aged 8 to 20 years (14.0 ± 4.9 years), were enrolled in Naples, Italy (unrelated patients NI and GM) and in Izmir, Turkey (sibling patients MK and AK), whose clinical data are summarized in Table 1. Diagnosis was based on clinical and cytogenetic data [3], [4], [5]. Also enrolled were 6 BS heteroygotes (three parental couples), aged 34 to 49 years (42.2 ± 5.2 years), and a total of 78 unrelated controls that were grouped in two age classes, i.e. 52

Results

The levels of leukocyte 8-OHdG in the four BS patients were increased vs. 40 controls in the same age range (4.8 ± 1.7 vs. 2.5 ± 1.0 mol 8-OHdG × 106/mol dG, p = 0.04) (Table 2). The leukocyte 8-OHdG levels in the six BS heterozygotes were superimposable with the data from 24 controls in the same age range.

The urinary levels of 8-OHdG in the four BS patients displayed a non-significant increase vs. 9 control data (7.0 ± 1.7 vs. 5.2 ± 1.3), whereas the BS heterozygotes failed to display any significant

Discussion

An established consensus relates the BS-associated genetic defect with impaired DNA metabolism, since the defective gene, BLM, encodes the RECQL3 protein, belonging to the RECQ family of helicases, required for the maintenance of genomic stability in organisms ranging from bacteria to humans and including RECQL2 (mutated in Werner syndrome), RECQL4 (mutated in Rothmund-Thomson syndrome), and the yeast proteins Sgslp and Rqh1p [1], [10]. Furthermore, BLM protein has been functionally related to

Acknowledgments

The present study, a part of the EUROS (European Research on Oxidative Stress) Project, was supported by the European Commission, DG XII, contract # BMH4-CT98-3107, and by the Italian Association for Fanconi Anaemia Research (AIRFA). Thanks are due to the Contributors to the EUROS Project, who were as follows: Clinicians contributing to patient and control recruitment: Maria A. Pisanti, Anna Saviano; Sample processing and analyses: Paolo Ciavolino, Francesca Gallucci, Virginia Rossi, Emilia

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