Understanding the basis of tubular aggregate myopathy

Tubular aggregate myopathy is an ultra-rare inherited genetic disorder that affects both men and women. The main symptom is muscle weakness accompanied by painful cramps, and many patients also experience excessive bleeding. The genetic mutations involved are known and may reside on three different genes: the ORAI1 gene, the STIM1 gene and the calsequestrin gene. There are many mutations on these genes and therefore the symptoms vary from patient to patient. The onset is often in preschool age and the symptoms significantly reduce the quality of life of affected subjects. The present study is preclinical and is centered on the understanding of the mechanisms in the cell that lead to muscle damage downstream of the genetic defect. This study will be based on a mouse that is affected by tubular aggregate myopathy due to a mutation on STIM1 identical to that found in some affected subjects and on cells derived from this mouse. The ultimate goal of this study is to fill the gaps in knowledge on the natural history of the disease and understand the mechanisms underlying the symptoms in order to refine the therapeutic tools hypothesized so far and bring a drug into clinical trials that can restore correct muscle and platelet function.