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© The Rockefeller University Press, 0021-9525/2000//235 $5.00
The Journal of Cell Biology, Volume 151, Number 2, , 2000 235-248

Indications for a Novel Muscular Dystrophy Pathway

: -Filamin, the Muscle-Specific Filamin Isoform, Interacts with Myotilin

Peter F.M. van der Ven^a, Sebastian Wiesner^a, Paula Salmikangas^b, Daniel Auerbach^c, Mirko Himmel^a, Stefan Kempa^a, Katrin Hayeß^a, Dirk Pacholsky^a, Anu Taivainen^b, Rolf Schröder^d, Olli Carpén^b, and Dieter O. Fürst^a

^a Department of Cell Biology, University of Potsdam, D-14471 Potsdam, Germany
^b Department of Pathology, Haartman Institute, University of Helsinki, SF-00290 Helsinki, Finland
^c Institute of Cell Biology, Swiss Federal Institute of Technology, Hönggerberg, CH-8093 Zürich, Switzerland
^d Department of Neurology, University Hospital Bonn, D-53127 Bonn, Germany
Department of Cell Biology, University of Potsdam, Lennéstr. 7a, D-14471 Potsdam, Germany.49 331 977 486149 331 977 4856

-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

© 2000 The Rockefeller University Press

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