Characterization of New Proteomic Biomarker Candidates in Mucopolysaccharidosis Type IVA

Abstract

Mucopolysaccharidosis type IVA (MPS IVA) is a lysosomal storage disease caused by mutations in the N-acetylgalactosamine-6-sulfatase (GALNS) gene. Skeletal dysplasia and the related clinical features of MPS IVA are caused by disruption of the cartilage and its extracellular matrix, leading to a growth imbalance. Enzyme replacement therapy (ERT) with recombinant human GALNS has yielded positive results in activity of daily living and endurance tests. However, no data have demonstrated improvements in bone lesions and bone grow thin MPS IVA after ERT, and there is no correlation between therapeutic efficacy and urine levels of keratan sulfate, which accumulates in MPS IVA patients. Using qualitative and quantitative proteomics approaches, we analyzed leukocyte samples from healthy controls (n = 6) and from untreated (n = 5) and ERT-treated (n = 8, sampled before and after treatment) MPS IVA patients to identify potential biomarkers of disease. Out of 690 proteins identified in leukocytes, we selected a group of proteins that were dysregulated in MPS IVA patients with ERT. From these, we identified four potential protein biomarkers, all of which may influence bone and cartilage metabolism: lactotransferrin, coronin 1A, neutral alpha-glucosidase AB, and vitronectin. Further studies of cartilage and bone alterations in MPS IVA will be required to verify the validity of these proteins as potential biomarkers of MPS IVA.

Plasma Proteomic Analysis in Morquio A Disease

“…After obtaining written informed consent, blood samples from MPS IVA patients were acquired for proteomic analysis of plasma from three Spanish centers of reference for MPS IVA: eight from untreated MPS IVA patients; and five from MPS IVA patients who had been undergoing ERT for a mean duration of 7 years, and from whom samples were taken 24 h before (ERT-a group) and 24 h after (ERT-b group) one of their weekly ERT infusions. All patients presented the classical phenotype as is shown in the previous study [ 32 ]. Another 6 blood samples were acquired from 6 healthy donors ( Figure 15 ).…”

“…From these ERT-treated patients, samples were acquired 24 h before (ERT-a) and 24 h after (ERT-b) one of their weekly infusions ( Figure 1 ). The demographic features of the participating MPS IVA patients have been previously described [ 32 ].…”

“…Proteomic analysis was performed as described previously by our group [ 32 ]. Plasma samples were first depleted as previously described [ 59 ].…”

“…Specific disease biomarkers identified using proteomics techniques could help improve diagnostic and prognostic precision and serve as key tools for the evaluation of treatment outcomes [ 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 ]. We recently characterized new proteomic biomarker candidates in leukocytes of MPS IVA patients [ 32 ]. However, in the present study we sought to identify disease biomarkers in body fluids that can be more easily sampled and feasibly incorporated into a clinical setting to increase diagnostic accuracy in patients with this disease.…”

Proteomics in Inherited Metabolic Disorders

“…Recently, we demonstrated that using a combination of shotgun proteomics with SWATH-MS [ 74 , 75 , 76 ] can provide useful information about mucopolysaccharidosis type IVA (MPS IVA). Moreover, this technique can be scaled to accommodate thousands of samples without compromising measurement precision.…”