Abstract Details

Title Heterozygous Missense Mutation of the ?-Sarcoglycan Gene Is Associated with a Novel Idiopathic Inflammatory Myopathy

Topic Muscle Disease/Neuromuscular Junction

Presentation(s) P07 - (-)

Poster/Presentation
Number 043

Objective

Background BACKGROUND: Patients with IIMs commonly present with a clinical phenotype of non-selective proximal upper and lower limb weakness associated with other organ involvement . About 80% IIMs develop myositis specific and/or associated autoantibodies (MSA/MAA). Specific haplotypes confer genetic predisposition to IIMs but little is known about involvement of other genes. Genome wide association studies have attempted to identify single nucleotide polymorphisms other than HLA that might be relevant to the pathogenesis of IIMs.

Design/Methods DESIGN/METHODS: We performed western blots of the patients' sera against normal skeletal muscle protein extracts and recombinant proteins, immunofluorescence against normal muscle tissue. Southern blot and DNA sequencing was performed on patients and controls and we used iterative threading assembly refinement and molecular dynamics simulation to obtain the 3D model of the protein and to study the effect of the mutation on the structure and dynamics of the protein.

Results RESULTS: The patients had peculiar phenotype characterised by symmetric distal weakness and quadriceps sparing; CK >2,000 IU/L; were seronegative for MSA and MAA. Muscle biopsies showed T and B-cell inflammation, plasma cells and deposits of MAC on sarcolemma and endomysial capillaries. The sera contained autoantibodies against ?/?/?-sarcoglycans. The patients responded to immunosuppressant therapy and plasma exchange. They were heterozygous for a missense mutation of the ?-sarcoglycan (exon 6), encoding the extracellular domain of the protein. However, the expression of the sarcoglycans was normal. Protein modelling of ?-sarcoglycan suggests that the mutation affects the conformation of the extacellular domain without affecting the membrane and intracellular portion.

Conclusions CONCLUSIONS: We have identified a missense mutation of the ?-sarcoglycan gene associated with anti-?/?/?-sarcoglycan autoantibodies. Co-localization of anti-?/?/?-sarcoglycan autoantibodies with MAC, response to immunosuppressant therapy and molecular modelling support their pathogenetic role.

Authors/Disclosures
Chiara Marini-Bettolo (Newcastle University) PRESENTER	Chiara Marini-Bettolo has nothing to disclose.
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