Characterization of the R7S mutation of Heat Shock Protein HSPB3 and of two novel mutations found in patients suffering of congenital myopathy: understanding the mechanisms leading to disease

HSPB3 is a poorly characterized member of the small HSP/HSPB family (HSPB1-HSPB10) that forms a complex with HSPB2. The HSPB2/HSPB3 complex is induced during muscle differentiation and plays a role in muscle maintenance. Recently the R7S mutation in HSPB3 has been associated with distal hereditary motor neuropathy type 2C (dHMN 2C). Here, we describe the identification of two new mutations in HSPB3 found in patients affected by congenital myopathy. Our proposal focuses on the detailed characterization in vitro, in motor neurons and myoblasts of these HSPB3 mutants and how they might affect the stability and function of HSPB3 and the HSPB2/HSPB3 complex. Moreover, HSPB2 enhances the kinase activity of myotonic dystrophy protein kinase (DMPK), whose mutations are associated with myotonic dystrophy and whose hyperactivation/overexpression also affects muscle function/viability. We will investigate in how far altered mutant HSPB3/HSPB2 binding can interfere with DMPK activity and whether/how this may contribute to disease. Our proposal will elucidate on HSPB3 and HSPB2 function in both motor neurons and myoblasts and will shed light on how mechanistically the mutations in HSPB3 affect the function and viability of these cell types, leading to disease. Understanding the molecular mechanisms of disease represents the first step towards the design of any therapeutic approach. Besides, we will extend the mutation analysis of the HSPB3 gene to a larger cohort of myopathic patients in order to identify the same or other mutations in HSPB3 in other myopathic patients. This will also contribute to better understand the association between HSPB3 mutations and motor neuropathy and/or congenital myopathy.