Oxidative profile exhibited by Mucopolysaccharidosis type IVA patients at diagnosis: Increased keratan urinary levels

Bruna Donida; Desirèe P Marchetti; Carlos Eduardo Diaz Jacques; Graziela Ribas; Marion Deon; Paula Manini; Helen Tais da Rosa; Dinara Jaqueline Moura; Jenifer Saffi; Roberto Giugliani; Carmen Regla Vargas

doi:10.1016/j.ymgmr.2017.04.005

Oxidative profile exhibited by Mucopolysaccharidosis type IVA patients at diagnosis: Increased keratan urinary levels

Mol Genet Metab Rep. 2017 Apr 25:11:46-53. doi: 10.1016/j.ymgmr.2017.04.005. eCollection 2017 Jun.

Authors

Bruna Donida¹, Desirèe P Marchetti¹, Carlos Eduardo Diaz Jacques¹, Graziela Ribas^{2

3}, Marion Deon^{4

3}, Paula Manini⁵, Helen Tais da Rosa¹, Dinara Jaqueline Moura⁵, Jenifer Saffi⁵, Roberto Giugliani^{3

6}, Carmen Regla Vargas^{1

4

3}

Affiliations

¹ Programa de Pós-Graduação em Ciências Biológicas, Bioquímica, UFRGS, Porto Alegre, RS, Brazil.
² Programa de Pós Graduação em Saúde da Criança e do Adolescente, UFRGS, Porto Alegre, RS, Brazil.
³ Serviço de Genética Médica, HCPA, Porto Alegre, RS, Brazil.
⁴ Programa de Pós-Graduação em Ciências Farmacêuticas, UFRGS, Porto Alegre, RS, Brazil.
⁵ Laboratório de Genética Toxicológica, UFCSPA, Porto Alegre, RS, Brazil.
⁶ Departamento de Genética, e Programa de Pós-Graduação em Genética e Biologia Molecular, Instituto de Biociências, UFRGS, Porto Alegre, RS, Brazil.

Abstract

Morquio A disease (Mucopolysaccharidosis type IVA, MPS IVA) is one of the 11 mucopolysaccharidoses (MPSs), a heterogeneous group of inherited lysosomal storage disorders (LSDs) caused by deficiency in enzymes need to degrade glycosaminoglycans (GAGs). Morquio A is characterized by a decrease in N-acetylgalactosamine-6-sulfatase activity and subsequent accumulation of keratan sulfate and chondroitin 6-sulfate in cells and body fluids. As the pathophysiology of this LSD is not completely understood and considering the previous results of our group concerning oxidative stress in Morquio A patients receiving enzyme replacement therapy (ERT), the aim of this study was to investigate oxidative stress parameters in Morquio A patients at diagnosis. It was studied 15 untreated Morquio A patients, compared with healthy individuals. The affected individuals presented higher lipid peroxidation, assessed by urinary 15-F2t-isoprostane levels and no protein damage, determined by sulfhydryl groups in plasma and di-tyrosine levels in urine. Furthermore, Morquio A patients showed DNA oxidative damage in both pyrimidines and purines bases, being the DNA damage positively correlated with lipid peroxidation. In relation to antioxidant defenses, affected patients presented higher levels of reduced glutathione (GSH) and increased activity of glutathione peroxidase (GPx), while superoxide dismutase (SOD) and glutathione reductase (GR) activities were similar to controls. Our findings indicate that Morquio A patients present at diagnosis redox imbalance and oxidative damage to lipids and DNA, reinforcing the idea about the importance of antioxidant therapy as adjuvant to ERT, in this disorder.

Keywords: 8-OHdG, 8-hydroxy-2′-deoxyguanosine; Cr, creatinine; DI, damage index; DTNB, 5,5′-dithiobis(2-nitrobenzoic acid); ELISA, enzyme-linked immunoassay; ERT, enzyme replacement therapy; Endo III, endonuclease III; FU, fluorescence units; GAGs, glycosaminoglycans; GALNS, N-acetylgalactosamine-6-sulfatase; GCL, glutamate cysteine ligase; GCLC, catalytic subunit of GCL; GPx, glutathione peroxidase; GR, glutathione reductase; GSH, reduced glutathione; GSSG, glutathione oxidized; H2O2, hydrogen peroxide; IEM, inborn errors of metabolism; Keratan sulfate; LPS, lipopolysaccharide; LSDs, lysosomal storage disorders; MPSs, mucopolysaccharidoses; Morquio A syndrome; Mucopolysaccharidosis type IVA; N-acetyl-galactosamine-6-sulfatase; OH•, hydroxyl radical; Oxidative stress; ROS, reactive oxygen species; SEM, standard error of the mean; SOD, superoxide dismutase; TLR4, Toll Like Receptor 4; TNB, tionitrobenzoic acid; mRNA, messenger ribonucleic acid.