Mutations in myotilin cause myofibrillar myopathy

Background and Objective: The term myofibrillar myopathy (MFM) is a noncommittal term for a pathologic pattern of myofibrillar dissolution associated with accumulation of myofibrillar degradation products and ectopic expression of multiple proteins. Ultrastructural studies implicate the Z-disk as the site of the initial pathologic change, and mutations in two Z-disk-related proteins, desmin and αB-crystallin, have been identified in a minority of patients with MFM. The authors' objective was to determine whether mutations in myotilin, a key Z-disk component and the disease protein in limb-girdle muscular dystrophy (LGMD) 1A, are another cause of MFM. Methods: The authors used histochemical, immunocytochemical, ultrastructural, and mutation analysis. Results: The authors detected four missense mutations in 6 of 57 patients with MFM in the serine-rich exon 2 of MYOT, where the two previously identified LGMD1A mutations are located. Three mutations were novel, and one had been previously identified in LGMD1A. Each patient had evidence for neuropathy, and at least three kinships had associated cardiomyopathy. Distal weakness greater than proximal weakness was present in three patients. Except for minor differences, the morphologic features were similar to those in other patients with MFM. Conclusions: 1) Mutations in myotilin cause MFM; 2) exon 2 of MYOT is a hotspot for mutations; 3) peripheral neuropathy, cardiomyopathy, and distal weakness greater than proximal weakness are part of the spectrum of myotilinopathy; 4) not all cases of myotilinopathy have a limb-girdle phenotype; and 5) the molecular basis of the majority of MFM cases remains to be discovered.