Original Article

Indications for a Novel Muscular Dystrophy Pathway: -Filamin, the Muscle-specific Filamin Isoform, Interacts with Myotilin

Correspondence to: Peter F.M. van der Ven, Department of Cell Biology, University of Potsdam, Lennéstr. 7a, D-14471 Potsdam, Germany. Tel:49 331 977 4856 Fax:49 331 977 4861

-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 -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 -filamin. The two Ig-like domains of the recently described -actinin–binding Z-disc protein myotilin were found to interact directly with this filamin domain, indicating that the amino-terminal end of -filamin may be indirectly anchored to -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.

Key Words: filamin, myotilin, limb-girdle muscular dystrophy, myofibrils, Z-disc proteins

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