Plasma Proteomic Analysis in Morquio A Disease.

José V Álvarez,Sofía Barbosa-Gouveia,María Pilar Chantada-Vázquez,Shunji Tomatsu,Susana B Bravo,Olalla López-Suarez,Francisco J Otero-Espinar,Cristóbal Colón,María L Couce

doi:10.3390/ijms22116165

Abstract

Mucopolysaccharidosis type IVA (MPS IVA) is a lysosomal disease caused by mutations in the gene encoding the enzymeN-acetylgalactosamine-6-sulfate sulfatase (GALNS), and is characterized by systemic skeletal dysplasia due to excessive storage of keratan sulfate (KS) and chondroitin-6-sulfate in chondrocytes. Although improvements in the activity of daily living and endurance tests have been achieved with enzyme replacement therapy (ERT) with recombinant human GALNS, recovery of bone lesions and bone growth in MPS IVA has not been demonstrated to date. Moreover, no correlation has been described between therapeutic efficacy and urine levels of KS, which accumulates in MPS IVA patients. The objective of this study was to assess the validity of potential biomarkers proposed by other authors and to identify new biomarkers. To identify candidate biomarkers of this disease, we analyzed plasma samples from healthy controls (n=6) and from untreated (n=8) and ERT-treated (n=5, sampled before and after treatment) MPS IVA patients using both qualitative and quantitative proteomics analyses. The qualitative proteomics approach analyzed the proteomic profile of the different study groups. In the quantitative analysis, we identified/quantified 215 proteins after comparing healthy control untreated, ERT-treated MPSIVA patients. We selected a group of proteins that were dysregulated in MPS IVA patients. We identified four potential protein biomarkers, all of which may influence bone and cartilage metabolism: fetuin-A, vitronectin, alpha-1antitrypsin, and clusterin. Further studies of cartilage and bone samples from MPS IVA patients will be required to verify the validity of these proteins as potential biomarkers of MPS IVA.

Highlights

Mucopolysaccharidosis type IVA (MPS IVA, OMIM #253000) or Morquio A syndrome is an autosomal recessive disease caused by mutations in the gene encoding the enzymeN-acetylgalactosamine-6-sulfate sulfatase (GALNS) gene
While bone cartilage samples are the best samples in which to search for candidate biomarkers of MPS IVA, the objective of this study was to assess the validity of candidate plasma biomarkers proposed in previous studies and to search for new biomarkers
We focused on potential biomarkers in plasma, which we identified using two proteomics techniques: qualitative LC-MS/MS and a quantitative assay that compared protein expression between controls and untreated or enzyme replacement therapy (ERT)-treated

Summary

Introduction

Mucopolysaccharidosis type IVA (MPS IVA, OMIM #253000) or Morquio A syndrome is an autosomal recessive disease caused by mutations in the GALNS gene. This molecular defect results in a deficiency in the enzyme N-acetylgalactosamine-6-sulfate sulfatase (GALNS, E.C.3.1.6.4) [1,2,3], which degrades the specific glycosaminoglycans(GAGs) keratan sulfate (KS) and chondroitin-6-sulfate (C6S) [4,5,6,7]. These GAGs accumulate in multiple tissues, mainly bone, cartilage, heart valves, and cornea, leading to progressive systemic skeletal dysplasia [8,9]. Respiratory failure is the primary cause of death, which typically occurs during the second or third decades of life [15,16]

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