In line, the co-submitted work of the group of Rosenzweig32 using NMR and biochemical analysis shows that the LGMD pathogenic mutants are unaffected in substrate interactions and chaperoning but rather lead to unregulated binding and hyperactivation of the ATPase of Hsp70 in the absence of clients. This evidence concerns the gene DNAH8 and limb-girdle muscular dystrophy.