IDENTIFICATION AND FUNCTIONAL CHARACTERISATION OF COL6A GENES MUTATIONS IN COLLAGEN TYPE VI MYOPATHIES AIMED AT RECRUITING ELIGIBLE PATIENTS FOR A CYCLOSPORINE A THERAPEUTIC TRIAL

We aim at fully characterising the genetic defect in 35 patients affected with Ullrich congenital muscular dystrophy (UCMD) and Bethlem myopathy (BM) in order to make them eligible for a future clinical trial. UCMD and BM are hereditary muscle disorders of variable severity due to mutations in the COL6 genes. Those genes encode for the collagen VI protein, which is essential for optimal muscle function. The identification of the underlying mutation in UCMD/BM patients is difficult and complex as high-demanding, money and time consuming procedure. These characteristics have hampered the chance of a wide and extensive genetic analysis in UCMD/BM patients worldwide. A recent collaborative study, also involving our group, has demonstrated that cells from UCMD/BM patients display a mitochondrial dysfunction that causes an increased apoptosis. These defects were however normalized by a treatment with cyclosporin A (CsA) or with CsA derivatives that lack immunosuppressive activity. This finding has opened concrete possibilities of a pharmacological therapy for these patients. A pilot trial with CsA, involving five UCMD/BM patients, has been already carried on with promising results. In order to proceed with an enlarged trial, the genetic characterisation is mandatory for patients to be enrolled. We aims at i) identifying all COL6 genes mutations in patients considered clinically eligible for a therapeutic trial; ii) confirming the pathological effect of the identified mutations. Genetic definition is required for including patients in a clinical trial. The output of the project is to provide a cohort of fully characterised patients that will be eligible for being recruited in future clinical trials.