Dataset Information

N-terminal ? Dystroglycan (?DG-N): A Potential Serum Biomarker for Duchenne Muscular Dystrophy.

ABSTRACT: BACKGROUND:Duchenne Muscular Dystrophy (DMD) is a severe, progressive, neuromuscular disorder of childhood. While a number of serum factors have been identified as potential biomarkers of DMD, none, as yet, are proteins within the dystrophin-associated glycoprotein (DAG) complex. OBJECTIVE:We have developed an immobilized serum ELISA assay to measure the expression of a constitutively cleaved and secreted component of the DAG complex, the N-terminal domain of ? dystroglycan (?DG-N), and assayed relative expression in serum from muscular dystrophy patients and normal controls. METHODS:ELISAs of immobilized patient or mouse serum and Western blots were used to assess ?DG-N expression. RESULTS:Immobilization of diluted serum on ELISA plates was important for this assay, as methods to measure serum ?DG-N in solution were less robust. ?DG-N ELISA signals were significantly reduced in DMD serum (27±3% decrease, n?=?9, p?

SUBMITTER: Crowe KE

PROVIDER: S-EPMC5541672 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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N-terminal α Dystroglycan (αDG-N): A Potential Serum Biomarker for Duchenne Muscular Dystrophy.

Crowe Kelly E KE Shao Guohong G Flanigan Kevin M KM Martin Paul T PT

Journal of neuromuscular diseases 20160501 2

<h4>Background</h4>Duchenne Muscular Dystrophy (DMD) is a severe, progressive, neuromuscular disorder of childhood. While a number of serum factors have been identified as potential biomarkers of DMD, none, as yet, are proteins within the dystrophin-associated glycoprotein (DAG) complex.<h4>Objective</h4>We have developed an immobilized serum ELISA assay to measure the expression of a constitutively cleaved and secreted component of the DAG complex, the N-terminal domain of α dystroglycan (αDG-N ...[more]

PMID: 27854211

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Project description:BACKGROUND:Duchenne muscular dystrophy (DMD) is a fatal disease for which no cure is available. Clinical trials have shown to be largely underpowered due to inter-individual variability and noisy outcome measures. The availability of biomarkers able to anticipate clinical benefit is highly needed to improve clinical trial design and facilitate drug development. METHODS:In this study, we aimed to appraise the value of protein biomarkers to predict prognosis and monitor disease progression or treatment outcome in patients affected by DMD. We collected clinical data and 303 blood samples from 157 DMD patients in three clinical centres; 78 patients contributed multiple blood samples over time, with a median follow-up time of 2 years. We employed linear mixed models to identify biomarkers that are associated with disease progression, wheelchair dependency, and treatment with corticosteroids and performed survival analysis to find biomarkers whose levels are associated with time to loss of ambulation. RESULTS:Our analysis led to the identification of 21 proteins whose levels significantly decrease with age and nine proteins whose levels significantly increase. Seven of these proteins are also differentially expressed in non-ambulant patients, and three proteins are differentially expressed in patients treated with glucocorticosteroids. Treatment with corticosteroids was found to partly counteract the effect of disease progression on two biomarkers, namely, malate dehydrogenase 2 (MDH2, P = 0.0003) and ankyrin repeat domain 2 (P = 0.0005); however, patients treated with corticosteroids experienced a further reduction on collagen 1 serum levels (P = 0.0003), especially following administration of deflazacort. A time to event analysis allowed to further support the use of MDH2 as a prognostic biomarker as it was associated with an increased risk of wheelchair dependence (P = 0.0003). The obtained data support the prospective evaluation of the identified biomarkers in natural history and clinical trials as exploratory biomarkers. CONCLUSIONS:We identified a number of serum biomarkers associated with disease progression, loss of ambulation, and treatment with corticosteroids. The identified biomarkers are promising candidate prognostic and surrogate biomarkers, which may support drug developers if confirmed in prospective studies. The serum levels of MDH2 are of particular interest, as they correlate with disease stage and response to treatment with corticosteroids, and are also associated with the risk of wheelchair dependency and pulmonary function.

Dataset Information

N-terminal ? Dystroglycan (?DG-N): A Potential Serum Biomarker for Duchenne Muscular Dystrophy.

Publications

N-terminal α Dystroglycan (αDG-N): A Potential Serum Biomarker for Duchenne Muscular Dystrophy.

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