Mutations in the N-terminal Actin-Binding Domain of Filamin C Cause a Distal Myopathy

Abstract

Linkage analysis of the dominant distal myopathy we previously identified in a large Australian family demonstrated one significant linkage region located on chromosome 7 and encompassing 18.6 Mbp and 151 genes. The strongest candidate gene was FLNC because filamin C, the encoded protein, is muscle-specific and associated with myofibrillar myopathy. Sequencing of FLNC cDNA identified a c.752T>C (p.Met251Thr) mutation in the N-terminal actin-binding domain (ABD); this mutation segregated with the disease and was absent in 200 controls. We identified an Italian family with the same phenotype and found a c.577G>A (p.Ala193Thr) filamin C ABD mutation that segregated with the disease. Filamin C ABD mutations have not been described, although filamin A and filamin B ABD mutations cause multiple musculoskeletal disorders. The distal myopathy phenotype and muscle pathology in the two families differ from myofibrillar myopathies caused by filamin C rod and dimerization domain mutations because of the distinct involvement of hand muscles and lack of pathological protein aggregation. Thus, like the position of FLNA and B mutations, the position of the FLNC mutation determines disease phenotype. The two filamin C ABD mutations increase actin-binding affinity in a manner similar to filamin A and filamin B ABD mutations. Cell-culture expression of the c.752T>C (p.Met251)Thr mutant filamin C ABD demonstrated reduced nuclear localization as did mutant filamin A and filamin B ABDs. Expression of both filamin C ABD mutants as full-length proteins induced increased aggregation of filamin. We conclude filamin C ABD mutations cause a recognizable distal myopathy, most likely through increased actin affinity, similar to the pathological mechanism of filamin A and filamin B ABD mutations.

Loss of ALS-associated TDP-43 in zebrafish causes muscle degeneration, vascular dysfunction, and reduced motor neuron axon outgrowth

“…Filamin Ca was identified as the top hit of the up-regulated proteins. The importance of Filamin C for muscle integrity is supported by the observation that mutations in Filamin C lead to myofibrillar and distal myopathy in humans (38,39). Moreover, mutant analysis of Filamin C in Medaka and zebrafish support a conserved function in teleosts (40,41).…”

Integrins in the Development and Pathology of Skeletal Muscle

“…These mutations are localized in the N-terminal actin-binding domain of filamin C, and induce increased actin binding. However, unlike the situation in patients where mutations are in the C-terminus, no protein aggregates accumulate in myofibres, suggesting that the pathological mechanisms differs from those observed in patients with mutations in the dimerization domain (Duff et al, 2011).…”

Myofibrillar Myopathies and the Z-Disk Associated Proteins

“…Since this initial discovery five additional FLNC mutations have been identified of which two result in MFM [203,204] and three cause distal myopathies in which protein aggregates are not evident [205,206] (Table 6). …”

“…Pathology: abnormal myofibre size; internally located nuclei. Classified as distal myopathy [205] c.2695_2712del + GTTTGTins…”

“…Other studies: C2C12 show increased number of stress fibres and cell projections; FLNC-and Actin-positive aggregates were detected. Classified as distal myopathy [205] c.752T>C…”