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Title: The role of emerin in the pathogenesis of sporadic inclusion body myositis
Author: Marini Bettolo, Chiara
ISNI:       0000 0004 5918 537X
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2016
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Idiopathic Inflammatory Myopathies (IIMs) are a heterogeneous group of acquired diseases characterised by inflammation of the skeletal muscle. The most common forms are sporadic inclusion body myositis (sIBM), dermatomyositis, polymyositis, overlap syndormes and necrotising myopathy. Sporadic IBM is the most common acquired myopathy over the age of 50 years, however its pathogenesis remains largely unsolved and there is still debate on whether it is a primary inflammatory or a degenerative condition with secondary inflammatory component. I used an in silico approach to identify molecules of interest that might shed light on the pathogenesis of sIBM. Emerin, a nuclear envelope protein, resulted as one of the candidate molecules. To verify in silico analysis results I reviewed a cohort of patients with sIBM phenotype identified at Charing Cross Hospital. This review allowed me to select 10 sIBM patients and identify 3 further patients with sIBM-like phenotype and good response to steroids. The selected patients have been then tested through immunohistochemical, immunoblotting and sequencing studies. Immunohistochemistry studies using anti-emerin antibodies showed abnormal distribution of emerin in the sIBM patients but not in the 3 patients with sIBM-like phenotype. Interestingly, sequencing of the emerin gene identified missense mutations in the 5'-untranslated region. The three IBM-like patients were extensively studied and serum analysis allowed me to identify a novel autoantibody that proved to target the sarcoglycans. Sequencing of the sarcoglycans genes in the three patients identified a missense mutation in the β-sarcoglycan affecting the 3D-structure of the extracellular component. The identification of this novel autoantibody prompted a further pilot study to develop a diagnostic test to identify novel autoantibodies to sarcolemmal proteins. Variable positive reactivity against sarcolemmal proteins, suggestive of presence of autoantibodies against sarcolemmal proteins was identified through immunoblotting in the sera of 10 further IIM patients, but not in 9 controls. This study highlights the complexity behind the pathogenesis of IIM and importance of unified classification criteria. Although further studies on a larger scale will be needed I suggest that emerin immunolabeling could be used as diagnostic biomarker in patients with sIBM. In addition, a pilot study using of skeletal muscle protein extract revealed novel autoantibodies in IIM whose pathogenicity remains to be established.
Supervisor: Roncaroli, Federico ; Turkheimer, Federico Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral