Filamin C-related myopathies: pathology and mechanisms

Abstract

The term filaminopathy was introduced after a truncating mutation in the dimerization domain of filamin C (FLNc) was shown to be responsible for a devastating muscle disease. Subsequently, the same mutation was found in patients from diverse ethnical origins, indicating that this specific alteration is a mutational hot spot. Patients initially present with proximal muscle weakness, while distal and respiratory muscles become affected with disease progression. Muscle biopsies of these patients show typical signs of myofibrillar myopathy, including disintegration of myofibrils and aggregation of several proteins into distinct intracellular deposits. Highly similar phenotypes were observed in patients with other mutations in Ig-like domains of FLNc that result in expression of a noxious protein. Biochemical and biophysical studies showed that the mutated domains acquire an abnormal structure causing decreased stability and eventually becoming a seed for abnormal aggregation with other proteins. The disease usually presents only after the fourth decade of life possibly as a result of ageing-related impairments in the machinery that is responsible for disposal of damaged proteins. This is confirmed by mutations in components of this machinery that cause a highly similar phenotype. Transfection studies of cultured muscle cells reflect the events observed in patient muscles and, therefore, may provide a helpful model for testing future dedicated therapeutic strategies. More recently, FLNC mutations were also found in families with a distal myopathy phenotype, caused either by mutations in the actin-binding domain of FLNc that result in increased actin-binding and non-specific myopathic abnormalities without myofibrillar myopathy pathology, or a nonsense mutation in the rod domain that leads to RNA instability, haploinsufficiency with decreased expression levels of FLNc in the muscle fibers and myofibrillar abnormalities, but not to the formation of desmin-positive protein aggregates required for the diagnosis of myofibrillar myopathy.

Mutations in filamin C cause a new form of familial hypertrophic cardiomyopathy

“…In fact, analysis of skeletal muscle biopsies from two HCM patients showed a normal muscle fibre histology and biochemistry, and lacked any of the myopathological or electrophysiological abnormalities described in myofibrillar myopathy patients. These findings, together with previous reports showing that different mutations within the filamin C molecule result in different myopathological features 16 [19][20][21] . Similarly, mutations in FHL1, which usually cause skeletal muscle disease, have been shown to cause HCM with left ventricular diastolic dysfunction without skeletal muscle affection 22,23 .…”

“…Similarly, mutations in FHL1, which usually cause skeletal muscle disease, have been shown to cause HCM with left ventricular diastolic dysfunction without skeletal muscle affection 22,23 . This situation is closely parallel to that of the FLNC mutations described in the present work, which are mainly clustered on the N-and C-terminal parts of the protein, but none of them overlap with previously described mutations causing myofibrillar myopathy 16 . Nevertheless, and taking into account that filamin C interacts with many proteins involved in muscle function, we can speculate that some mutations may have more impact in cardiac muscle or in skeletal muscle, depending on whether they affect specific domains or binding surfaces of this sarcomeric protein.…”

A Novel Structural Unit in the N-terminal Region of Filamins

“…All three FLN genes (FLNA, FLNB, and FLNC) are essential in mouse and truncation or substitution mutations cause developmental defects in humans (1,2) (Fig. 1).…”

Label-free Quantitative Protein Profiling of vastus lateralis Muscle During Human Aging

“…Filamin-C is a muscle specific actin-binding protein, that interacts with both Z-disc proteins and sarcolemma-associated proteins and is involved in membrane anchorage of myofibrils. Notably, filamin C mutations are responsible for a myofibrillar myopathy, which preferentially occurs as a result of aging-related impairments in the proteolytic machinery (41).…”