Indications for a Novel Muscular Dystrophy Pathway

Abstract

γ-Filamin, also called ABP-L, is a filamin isoform that is specifically expressed in striated muscles, where it is predominantly localized in myofibrillar Z-discs. A minor fraction of the protein shows subsarcolemmal localization. Although γ-filamin has the same overall structure as the two other known isoforms, it is the only isoform that carries a unique insertion in its immunoglobulin (Ig)-like domain 20. Sequencing of the genomic region encoding this part of the molecule shows that this insert is encoded by an extra exon. Transient transfections of the insert-bearing domain in skeletal muscle cells and cardiomyocytes show that this single domain is sufficient for targeting to developing and mature Z-discs. The yeast two-hybrid method was used to identify possible binding partners for the insert-bearing Ig-like domain 20 of γ-filamin. The two Ig-like domains of the recently described α-actinin–binding Z-disc protein myotilin were found to interact directly with this filamin domain, indicating that the amino-terminal end of γ-filamin may be indirectly anchored to α-actinin in the Z-disc via myotilin. Since defects in the myotilin gene were recently reported to cause a form of autosomal dominant limb-girdle muscular dystrophy, our findings provide a further contribution to the molecular understanding of this disease.

Novel Mutation in FLNC (Filamin C) Causes Familial Restrictive Cardiomyopathy

“…To perform these tasks, Filamin C has been demonstrated to bind with a multitude of other sarcomeric and intercalated disk components. V2297 is located in domain 20, part of the carboxy-terminal structure of FLNC which has been defined as the interaction site for Xin 25 , KY 26 , myotilin 27 , and multiple cadherins. 28,29 Although the disruptions in the amino-terminal actin binding domains that lead to the skeletal muscle-centric myofibrillar and distal myopathy are mechanistically understood, the list of interactors in the carboxy-terminal region is likely incomplete.…”

Myozenin: An alpha -actinin- and gamma -filamin-binding protein of skeletal muscle Z lines

“…This site is near, but distinct from, the muscle-specific repeat 20 interdomain insertion that binds myotilin and is important for localization of ␥-filamin at Z lines (32). It is interesting to note that filamin repeat 24 contains sequences responsible for dimerization.…”

Loss of muscle-specific RING-finger 3 predisposes the heart to cardiac rupture after myocardial infarction

“…Filamins act as actin-cross-linking proteins and participate in multiple cellular processes, including cell-cell and cell matrix connections, mechanoprotection, and various signaling networks (23). ␥-filamin localizes to the Z-discs of the sarcomere, where it interacts with calsarcin/myozenin (24,25) and myotilin (26), as well as to the muscle sarcolemma where it associates with ␦-and ␥-sarcoglycan (26,27). A dominant form of myofibrillar myopathy has been ascribed to a mutation in the FLNC gene that results in ␥-filamin aggregates, altered distribution of myotilin and the dystrophin-sarcoglycan complex, and myofibrillar degeneration (28).…”