Indications for a novel muscular dystrophy pathway: gamma-filamin, the muscle-specific filamin isoform, interacts with myotilin

gamma -Filamin, also called ABP-L, is a filamin isororm that is specificall y expressed in striated muscles, where it is predominantly localized in myo fibrillar Z-discs. A minor fraction of the protein shows subsarcolemmal loc alization. Although gamma -filamin has the same overall structure as the tw o other known isoforms, it is the only isoform that carries a unique insert ion in its immunoglobulin (Ig)-like domain 20. Sequencing of the genomic re gion encoding this part of the molecule shows that this insert is encoded b y an extra exon. Transient transfections of the insert-bearing domain in sk eletal muscle cells and cardiomyocytes show that this single domain is suff icient for targeting to developing and mature Z-discs. The yeast two-hybrid method was used to identify possible binding partners for the insert-beari ng Ig-like domain 20 of gamma -filamin. The two Ig-like domains of the rece ntly described alpha -actinin-binding Z-disc protein myotilin were found to interact directly with this filamin domain, indicating that the amino-term inal end of gamma -filamin may be indirectly anchored to alpha -actinin in the Z-disc via myotilin. Since defects in the myotilin gene were recently r eported to cause a form of autosomal dominant limb-girdle muscular dystroph y, our findings provide a further contribution to the molecular understandi ng of this disease.