Key result
The mutated filamin C polypeptide (W2710X) is less stable, fails to dimerize properly, and forms aggregates in vitro and in cultured cells without associating with wild-type filamin.
The W2710X mutation in FLNC causes filaminopathy by destabilizing the dimerization domain, leading to improper dimerization and massive protein aggregation.
Provides mechanistic insight into FLNC cardiomyopathy; hypothesis-generating and requires in vivo validation before any clinical consideration.
Myofibrillar myopathy (MFM) is a pathologically defined group of hereditary human muscle diseases, characterized by focal myofibrillar destruction and cytoplasmic aggregates that contain several Z-disc-related proteins. The previously reported MFM-associated mutation (8130G --> A; W2710X) in the filamin C gene (FLNC) leads to a partial disturbance of the secondary structure of the dimerization domain of filamin C, resulting in massive protein aggregation in skeletal muscle fibers of the patients. Here, we provide a thorough characterization of the biochemical, biophysical and cellular properties of the mutated filamin C polypeptide. Our experiments revealed that the mutant dimerization domain is less stable and more susceptible to proteolysis. As a consequence, it does not dimerize properly and forms aggregates in vitro. Furthermore, the expression of mutant filamin in cultured cells results in the formation of protein aggregates. The mutant filamin does not associate with wild type filamin. These findings are of great importance to explain the pathomechanism of this disease.
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Löwe et al. (2007) studied Myofibrillar myopathy (filaminopathy). FLNC mutation (8130G --> A; W2710X) vs. Wild type filamin was evaluated on Protein aggregation and dimerization properties. The mutated filamin C polypeptide (W2710X) is less stable, fails to dimerize properly, and forms aggregates in vitro and in cultured cells without associating with wild-type filamin.
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